Derivatives of 4-piperazin-1-yl-4-benzo[B]thiophene suitable for the treatment of CNS disorders

ABSTRACT

A heterocyclic compound or a salt thereof represented by the formula (1): 
     
       
         
         
             
             
         
       
         
         
           
             where R 2  represents a hydrogen atom or a lower alkyl group; 
             A represents a lower alkylene group or lower alkenylene group; and 
             R 1  represents an aromatic group or a heterocyclic group. The compound of the present invention has a wide treatment spectrum for mental disorders including central nervous system disorders, no side effects and high safety.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 11/991,146, filed Feb. 28, 2008, now U.S. Pat. No. 8,071,600 which is a national phase application of International Application No. PCT/JP2006/317704, filed Aug. 31, 2006, and claims the priority of Japanese Application No. 2005-251055, filed Aug. 31, 2005, each being incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a novel heterocyclic compound.

BACKGROUND ART

Since causal factor of schizophrenia as well as of bipolar disorder, mood disorders and emotional disorders is heterogeneous, it is desirable that a drug has multiple pharmacological effects so as to develop wide treatment spectrum.

W02004/026864A1 discloses that a carbostyril derivative represented by the general formula:

(wherein A′ represents —(CH₂)_(m)CH₂—, —(CH₂)_(m)O—, etc.; m represents an integer of 1 to 4; and R^(A) represents a hydrogen atom, a C₁₋₄ alkyl group which may be substituted with 1 to 3 fluorine atoms, etc.) has D₂ receptor antagonist activity and serotonin 2A (5-HT_(2A)) receptor antagonist activity and it is effective for treatment of schizophrenia and other central nervous system disorders).

However, there is no description in WO2004/026864A1 that carbostyril derivatives described in the document have D₂ receptor partial agonist activity, 5-HT_(2A) receptor antagonist activity, α₁ receptor antagonist activity and serotonin uptake inhibitory activity together and have a wide treatment spectrum.

WO 2005/019215 A1 discloses the compounds represented by the following formula:

(wherein A is —(CH₂)_(m)CH₂—, —(CH₂)_(m)O— or the like; m is an integer of 2 to 5; D is N, C or the like; Z and Q are independently N, C or CH, provided that at least one of Z and Q is N; X and Y are independently C, N or the like, and the bond between X and Y is a single or double bond; R¹ is hydrogen, (C₁-C₃)alkyl group or the like; R⁴, R⁵, R⁶ and R⁷ each represents hydrogen, alkyl group or the like; and G represents a group of monocyclic or bicyclic compound), which bind to dopamine D₂ receptors. WO 2005/019215 A1 teaches that some compounds disclosed therein have an activity as partial agonists of D₂ receptors or an activity as antagonists of D₂ receptors, and may be effective for the treatment of schizophrenia and other central nervous system.

However, WO 2005/019215 A1 does not specifically disclose the compounds of the present invention.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide an antipsychotic drug which has a wider treatment spectrum, less side effects and excellent tolerability and safety as compared with well-known typical and atypical antipsychotic drugs.

The present inventors have conducted intensive studies on the above-described problem and consequently succeeded in synthesizing a novel compound which has dopamine D₂ receptor partial agonist activity (D₂ receptor partial agonist activity), serotonin 5-HT_(2A) receptor antagonist activity (5-HT_(2A) receptor antagonist activity) and adrenalin α₁ receptor antagonist activity (α₁ receptor antagonist activity) and further has serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect) together in addition to these effects. The present invention has been completed based on this finding.

There is provided a heterocyclic compound or a salt thereof represented by the formula (1):

where R² represents a hydrogen atom or a lower alkyl group; A represents a lower alkylene group or a lower alkenylene group; and R¹ represents a cyclo C3-C8 alkyl group, an aromatic group or a heterocyclic group selected from the group consisting of (I) to (IV) below:

(I) a cyclo C3-C8 alkyl group;

(II) an aromatic group selected from a phenyl group, a naphthyl group, a dihydroindenyl group and a tetrahydronaphthyl group;

(III) a saturated or unsaturated heteromonocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; and

(IV) a benzene fused heterocyclic group that has 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and that is selected from the group consisting of (1) a tetrahydroquinoxalinyl group, (2) a tetrahydroquinazolinyl group, (3) a dihydroquinazolinyl group, (4) an indolinyl group, (5) an indolyl group, (6) an isoindolinyl group, (7) a benzimidazolyl group, (8) a dihydrobenzimidazolyl group, (9) a tetrahydrobenzazepinyl group, (10) a tetrahydrobenzodiazepinyl group, (11) a hexahydrobenzazocinyl group, (12) a dihydrobenzoxazinyl group, (13) a dihydrobenzoxazolyl group, (14) a benzisoxazolyl group, (15) a benzoxadiazolyl group, (16) a tetrahydrobenzoxazepinyl group, (17) a dihydrobenzothiazinyl group, (18) a benzothiazolyl group, (19) a benzoxathiolyl group, (20) a chromenyl group, (21) a dihydrobenzofuryl group, (22) a carbazolyl group, (23) a dibenzofuryl group and (24) a quinoxalinyl group

wherein at least one group selected from the group consisting of the groups (1) to (66) below may be present as a substituent on the cyclo C3-C8 alkyl group, the aromatic group and the heterocyclic group represented by R¹:

(1) a lower alkyl group,

(2) a lower alkenyl group,

(3) a halogen substituted lower alkyl group,

(4) a lower alkoxy group,

(5) an aryloxy group,

(6) a lower alkylthio group,

(7) a halogen substituted lower alkoxy group,

(8) a hydroxy group,

(9) a protected hydroxy group,

(10) a hydroxy lower alkyl group,

(11) a protected hydroxy lower alkyl group,

(12) a halogen atom,

(13) a cyano group,

(14) an aryl group,

(15) a nitro group,

(16) an amino group,

(17) an amino group having a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group and a lower alkoxy carbonylamino lower alkanoyl group as a substituent,

(18) a lower alkanoyl group,

(19) an arylsulfonyl group that may have a lower alkyl group(s) on the aryl group,

(20) a carboxy group,

(21) a lower alkoxycarbonyl group,

(22) a carboxy lower alkyl group,

(23) a lower alkoxycarbonyl lower alkyl group,

(24) a lower alkanoylamino lower alkanoyl group,

(25) a carboxy lower alkenyl group,

(26) a lower alkoxycarbonyl lower alkenyl group,

(27) a carbamoyl lower alkenyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group as a substituent,

(28) a carbamoyl group that may have a group(s) selected from the group consisting of the groups (i) to (lxxviii) below as a substituent:

(i) a lower alkyl group,

(ii) a lower alkoxy group,

(iii) a hydroxy lower alkyl group,

(iv) a lower alkoxy lower alkyl group,

(v) an aryloxy lower alkyl group,

(vi) a halogen substituted lower alkyl group,

(vii) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an aroyl group and a carbamoyl group,

(viii) a cyclo C3-C8 alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group and a phenyl lower alkoxy group as a substituent,

(ix) a cyclo C3-C8 alkyl substituted lower alkyl group,

(x) a lower alkenyl group,

(xi) a carbamoyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, phenyl group that may have a lower alkyl group(s) and a phenyl group(s) that may have a lower alkoxy group(s) as a substituent,

(xii) a lower alkoxycarbonyl lower alkyl group,

(xiii) a furyl lower alkyl group (that may have a lower alkyl group(s) as a substituent) on the furyl group,

(xiv) a tetrahydrofuryl lower alkyl group,

(xv) a 1,3-dioxolanyl lower alkyl group,

(xvi) a tetrahydropyranyl lower alkyl group,

(xvii) a pyrrolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrrolyl group),

(xviii) a lower alkyl group substituted with a dihydropyrazolyl group that may have an oxo group(s),

(xix) a pyrazolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazolyl group),

(xx) an imidazolyl lower alkyl group,

(xxi) a pyridyl lower alkyl group,

(xxii) a pyrazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazinyl group),

(xxiii) a pyrrolidinyl lower alkyl group (that may have a group(s) selected from the group consisting of an oxo group(s) and a lower alkyl group as a substituent on the pyrrolidinyl group),

(xxiv) a piperidyl lower alkyl group (that may have a group(s) selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent on the piperidyl group),

(xxv) a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group),

(xxvi) a morpholinyl lower alkyl group,

(xxvii) a thienyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the thienyl group),

(xxviii) a thiazolyl lower alkyl group,

(xxix) a dihydrobenzofuryl lower alkyl group,

(xxx) a benzopyranyl lower alkyl group (that may have an oxo group(s) as a substituent on the benzopyranyl group),

(xxxi) a benzimidazolyl lower alkyl group,

(xxxii) an indolyl lower alkyl group that may have a lower alkoxycarbonyl group(s) on the lower alkyl group),

(xxxiii) an imidazolyl lower alkyl group that has a substituent(s) selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group on the lower alkyl group,

(xxxiv) a pyridyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group and a lower alkylthio lower alkyl group as a substituent,

(xxxv) a pyrrolidinyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group and an aroyl group as a substituent,

(xxxvi) a piperidyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group and an aroyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen atom as a substituent,

(xxxvii) a tetrahydrofuryl group that may have an oxo group(s),

(xxxviii) a hexahydroazepinyl group that may have an oxo group(s),

(xxxix) a pyrazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, an aryl group and a furyl group as a substituent,

(xl) a thiazolyl group,

(xli) a thiadiazolyl group that may have a lower alkyl group(s),

(xlii) an isoxazolyl group that may have a lower alkyl group(s),

(xliii) an indazolyl group,

(xliv) an indolyl group,

(xlv) a tetrahydrobenzothiazolyl group,

(xlvi) a tetrahydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and an oxo group as a substituent,

(xlvii) a quinolyl group that may have a lower alkyl group(s),

(xlviii) a benzodioxolyl lower alkyl group,

(xlix) an aryl group that may have a group(s) as a substituent, selected from the group consisting of

a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; an aryloxy group; an aryl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an aryl group; a pyrazolyl group; a pyrrolidinyl group that may have an oxo group(s); an oxazolyl group; an imidazolyl group that may have a lower alkyl group(s); a dihydrofuryl group that may have an oxo group(s); a thiazolidinyl lower alkyl group that may have an oxo group(s); an imidazolyl lower alkanoyl group and a piperidinylcarbonyl group,

(l) a cyano lower alkyl group,

(li) a dihydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an oxo group,

(lii) a halogen substituted lower alkylamino group,

(liii) a lower alkylthio lower alkyl group,

(liv) an amidino group that may have a lower alkyl group(s),

(lv) an amidino lower alkyl group,

(lvi) a lower alkenyloxy lower alkyl group,

(lvii) an arylamino group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group and a halogen substituted lower alkoxy group, on the aryl group,

(lviii) an aryl lower alkenyl group,

(lix) a pyridylamino group that may have a lower alkyl group(s),

(lx) an aryl lower alkyl group (that may have on the aryl group and/or the lower alkyl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, a carbamoyl group and a lower alkoxycarbonyl group as a substituent),

(lxi) a lower alkynyl group,

(lxii) an aryloxy lower alkyl group (that may have as a substituent on the aryl group a group(s) selected from the group consisting of a lower alkoxy group; a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkoxy group and a lower alkyl group; and a pyrrolidinyl group that may have an oxo group(s)),

(lxiii) an isoxazolidinyl group that may have an oxo group(s),

(lxiv) a dihydroindenyl group,

(lxv) an aryl lower alkoxy lower alkyl group,

(lxvi) a tetrahydropyranyl group,

(lxvii) an azetidinyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and an aroyl group,

(lxviii) an azetidinyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and aroyl group,

(lxix) a tetrazolyl group,

(lxx) an indolinyl group that may have an oxo group(s),

(lxxi) a triazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a lower alkylthio group,

(lxxii) an imidazolyl group that may have a carbamoyl group(s),

(lxxiii) an oxazolyl group that may have a lower alkyl group(s),

(lxxiv) an isothiazolyl group that may have a lower alkyl group(s),

(lxxv) a benzimidazolyl group,

(lxxvi) a dihydrobenzothiazolyl group that may have an oxo group(s),

(lxxvii) a thienyl group that may have a lower alkoxycarbonyl group(s), and

(lxxviii) an oxazolyl lower alkyl group that may have a lower alkyl group(s)

(29) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, an aryl group, an aryl lower alkyl group, an aroyl group and an amino substituted alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group) on the amino group,

(30) a lower alkyl group substituted with a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group,

(31) a thiocarbamoyl group that may have a lower alkyl group(s),

(32) a sulfamoyl group,

(33) an oxazolidinyl group that may have an oxo group(s),

(34) an imidazolidinyl group that may have a substituent(s) selected from the group consisting of an oxo group and a lower alkyl group,

(35) a pyrrolidinyl group that may have an oxo group(s),

(36) an imidazolyl group,

(37) a triazolyl group,

(38) an isoxazolyl group,

(39) a piperidyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an arylsulfonyl group, an oxo group, a hydroxy group, and an amino group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group and a lower alkanoylamino lower alkanoyl group,

(40) a piperidylcarbonyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group and an aroyl group may be present), a piperidyl group (on which a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group and an aroyl group may be present), piperazinyl group (on which a lower alkyl group(s) may be present as a substituent), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepinyl group (on which a lower alkyl group(s) may be present as a substituent), a pyridyl group, a pyridyloxy group, a pyridyl lower alkoxy group, a tetrahydroquinolyl group (on which an oxo group(s) may be present), a benzodioxolyl group, an aryl lower alkoxy group (that may have a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkoxy group on the aryl group), an aryl group (on which a group(s) selected from the group consisting of a halogen atom, a lower alkoxy group, a hydroxy group may be present), an aryloxy group (that may have on the aryl group a group(s) selected from the group consisting of a cyano group, a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkyl group), an aryl lower alkyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkyl group), and an aroyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom and a lower alkoxy group),

(41) a pyrrolidinylcarbonyl group that may have a group as a substituent, selected from the group consisting of a hydroxy lower alkyl group, a carbamoyl group, a hydroxy group, an amino group (that may have on the amino group a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group and an aroyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group), an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), an aryloxy group (that may have a halogen substituted lower alkoxy group(s) on the aryl group), an aryloxy lower alkyl group (that may have a halogen substituted lower alkoxy group(s) on the aryl group) and a tetrahydroquinolyl group (on which an oxo group(s) may be present),

(42) a piperazinylcarbonyl group that may have a group(s) as a substituent, selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), a piperidyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxolanyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have a phenyl group(s) as a substituent on the lower alkyl group), an imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group that may have a lower alkyl group(s) as a substituent, pyridyl group (that may have on the pyridyl group a group(s) selected from the group consisting of a lower alkyl group, a cyano group and a halogen substituted lower alkyl group as a substituent), a thieno[2,3-b]pyridyl group, an aryl group (on which a group(s) selected from the group consisting of a halogen atom and a lower alkyl group may be present), an aroyl group, a furyl carbonyl group, an aryl lower alkoxycarbonyl group and an oxo group,

(43) a hexahydroazepinylcarbonyl group,

(44) a hexahydro-1,4-diazepinylcarbonyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and a pyridyl group,

(45) a dihydropyrrolylcarbonyl group that may have a lower alkyl group(s),

(46) a thiomorpholinylcarbonyl group,

(47) a morpholinylcarbonyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group and an aryl group,

(48) a thiazolidinyl carbonyl group that may have an aryl group(s) that may have a group(s) selected from the group consisting of a lower alkoxy group and a cyano group,

(49) an azabicyclo[3.2.2]nonylcarbonyl group,

(50) an 8-azabicyclo[3.2.1]octylcarbonyl group that may have a halogen substituted or unsubstituted aryloxy group(s),

(51) an indolinylcarbonyl group,

(52) a tetrahydroquinolylcarbonyl group,

(53) a tetrahydropyrido[3.4-b]indolylcarbonyl group,

(54) a morpholinyl lower alkyl group,

(55) a piperazinyl lower alkyl group that may have a lower alkyl group(s) on the piperazinyl group,

(56) a morpholinylcarbonyl lower alkyl group,

(57) a piperazinylcarbonyl lower alkyl group that may have a lower alkyl group(s) on the piperazinyl group,

(58) an oxo group,

(59) an amino lower alkoxy group (that may have a lower alkyl group(s) on the amino group),

(60) a lower alkoxy lower alkoxy group,

(61) a piperazinyl group that may have a group(s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group and a lower alkoxycarbonyl group,

(62) a morpholinyl group,

(63) a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have a group(s) selected from the group consisting of an oxo group and an aryl group,

(64) a tetrahydropyridylcarbonyl group that may have a pyridyl group(s),

(65) an imidazolidinylcarbonyl group that may have a thioxo group(s), and

(66) a 1,4-dioxa-8-azaspiro[4.5]decanyl group.

The present invention provides a compound represented by the general formula (1), wherein

R¹ represents a cyclo C5-C6 alkyl group, an aromatic group or a heterocyclic group selected from the group consisting of (I) to (IV) below:

(I) a cyclo C5-C6 alkyl group;

(II) an aromatic group selected from a phenyl group, naphthyl group, dihydroindenyl group and tetrahydronaphthyl group;

(III) a saturated or unsaturated heteromonocyclic group that has 1 to 2 hetero atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom, and that is selected from the group consisting of a pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, isoxazolyl group, thiazolyl group, pyranyl group, and thienyl group; and

(IV) a benzene fused heterocyclic group that has 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom and that is selected from the group consisting of (1) a tetrahydroquinoxalinyl group, (2) a tetrahydroquinazolinyl group, (3) a dihydroquinazolinyl group, (4) an indolinyl group, (5) an indolyl group, (6) an isoindolinyl group, (7) a benzimidazolinyl group, (8) a dihydrobenzimidazolyl group, (9) a tetrahydrobenzazepinyl group, (10) a tetrahydrobenzodiazepinyl group, (11) a hexahydrobenzazocinyl group, (12) a dihydrobenzoxazinyl group, (13) a dihydrobenzoxazolyl group, (14) a benzisoxazolyl group, (15) a benzoxadiazolyl group, (16) a tetrahydrobenzoxazepinyl group, (17) a dihydrobenzothiazinyl group, (18) a benzothiazolyl group, (19) a benzoxathiolyl group, (20) a chromenyl group, (21) a dihydrobenzofuryl group, (22) a carbazolyl group, (23) a dibenzofuryl group, and (24) a quinoxalinyl group wherein, on the aromatic group and the heterocyclic group represented by R¹, 1 to 5 groups selected from the group consisting of the groups (1) to (66) below may be present as a substituent(s):

(1) a lower alkyl group,

(2) a lower alkenyl group,

(3) a halogen substituted lower alkyl group,

(4) a lower alkoxy group,

(5) a phenoxy group,

(6) a lower alkylthio group,

(7) a halogen substituted lower alkoxy group,

(8) a hydroxy group,

(9) a phenyl lower alkoxy group,

(10) a hydroxy lower alkyl group,

(11) a lower alkoxy lower alkyl group,

(12) a halogen atom,

(13) a cyano group,

(14) a phenyl group,

(15) a nitro group,

(16) an amino group,

(17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group and a lower alkoxycarbonylamino lower alkanoyl group as a substituent(s),

(18) a lower alkanoyl group,

(19) a phenylsulfonyl group that may have a single lower alkyl group on the phenyl group,

(20) a carboxy group,

(21) a lower alkoxycarbonyl group,

(22) a carboxy lower alkyl group,

(23) a lower alkoxycarbonyl lower alkyl group,

(24) a lower alkanoylamino lower alkanoyl group,

(25) a carboxy lower alkenyl group,

(26) a lower alkoxycarbonyl lower alkenyl group,

(27) a carbamoyl lower alkenyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a lower alkyl group substituted with 1 to 3 halogen atoms as a substituent(s),

(28) a carbamoyl group that may have 1 to 2 groups selected from the group consisting of the groups

(i) to (lxxviii) below as a substituent(s):

(i) a lower alkyl group,

(ii) a lower alkoxy group,

(iii) a hydroxy lower alkyl group,

(iv) a lower alkoxy lower alkyl group,

(v) an phenoxy lower alkyl group,

(vi) a halogen substituted lower alkyl group,

(vii) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group and a carbamoyl group,

(viii) a cyclo C3-C8 alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group and a phenyl lower alkoxy group as a substituent(s),

(ix) a cyclo C3-C8 alkyl substituted lower alkyl group,

(x) a lower alkenyl group,

(xi) a lower alkyl group having 1 to 2 carbamoyl groups that may have 1 to 2 groups as a substituent(s) selected from the group consisting of a lower alkyl group, a phenyl group that may have a single lower alkyl group and a phenyl group that may have a single lower alkoxy group,

(xii) a lower alkyl group having 1 to 2 lower alkoxy carbonyl groups,

(xiii) a furyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the furyl group),

(xiv) a tetrahydrofuryl lower alkyl group,

(xv) a 1,3-dioxolanyl lower alkyl group,

(xvi) a tetrahydropyranyl lower alkyl group,

(xvii) a pyrrolyl lower alkyl group (that may have 1 to 2 lower alkyl groups on the pyrrolyl group as a substituent(s)),

(xviii) a lower alkyl group substituted with a dihydropyrazolyl group that may have a single oxo group,

(xix) a pyrazolyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrazolyl group),

(xx) an imidazolyl lower alkyl group,

(xxi) a pyridyl lower alkyl group,

(xxii) a pyrazinyl lower alkyl group (that may have 1 to 3 (preferably 1) lower alkyl groups as a substituent(s) on the pyrazinyl group),

(xxiii) a pyrrolidinyl lower alkyl group (that may have 1 to 2 groups selected from the group consisting of an oxo group and a lower alkyl group as a substituent(s) on the pyrrolidinyl group),

(xxiv) a piperidyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent(s) on the piperidyl group),

(xxv) a piperazinyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the piperazinyl group),

(xxvi) a morpholinyl lower alkyl group,

(xxvii) a thienyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the thienyl group),

(xxviii) a thiazolyl lower alkyl group,

(xxix) a dihydrobenzofuryl lower alkyl group,

(xxx) a benzopyranyl lower alkyl group (that may have a single oxo group as a substituent on the benzopyranyl group),

(xxxi) a benzimidazolyl lower alkyl group,

(xxxii) an indolyl lower alkyl group that may have 1 to 3 lower alkoxycarbonyl groups on the lower alkyl group),

(xxxiii) an imidazolyl lower alkyl group that has 1 to 3 substituents selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group, on the lower alkyl group,

(xxxiv) a pyridyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group and a lower alkylthio lower alkyl group as a substituent(s),

(xxxv) a pyrrolidinyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group and a benzoyl group as a substituent(s),

(xxxvi) a piperidyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group and a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent(s) on the phenyl group),

(xxxvii) a tetrahydrofuryl group that may have a single oxo group

(xxxviii) a hexahydroazepinyl group that may have a single oxo group,

(xxxix) a pyrazolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group and a furyl group as a substituent(s),

(xl) a thiazolyl group,

(xli) a thiadiazolyl group that may have 1 to 3 lower alkyl groups,

(xlii) an isoxazolyl group that may have 1 to 3 lower alkyl groups,

(xliii) an indazolyl group,

(xliv) an indolyl group,

(xlv) a tetrahydrobenzothiazolyl group,

(xlvi) a tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and an oxo group as a substituent(s),

(xlvii) a quinolyl group that may have 1 to 3 lower alkyl groups,

(xlviii) a benzodioxolyl lower alkyl group,

(xlix) a phenyl group or naphthyl group that may have 1 to 3 groups as a substituent(s), selected from the group consisting of

a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; a phenyloxy group; a phenyl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a phenyl group; a pyrazolyl group; a pyrrolidinyl group that may have a single oxo group; oxazolyl group; an imidazolyl group that may have 1 to 3 lower alkyl groups; a dihydrofuryl group that may have a single oxo group; thiazolidinyl lower alkyl group that may have two oxo groups; imidazolyl lower alkanoyl group and piperidinylcarbonyl group,

(l) a cyano lower alkyl group,

(li) a dihydroquinolyl group that may have 1 to 3 group(s) selected from the group consisting of a lower alkyl group and oxo group,

(lii) a halogen substituted lower alkylamino group,

(liii) a lower alkylthio lower alkyl group,

(liv) an amidino group that may have a lower alkyl group,

(lv) an amidino lower alkyl group,

(lvi) a lower alkenyloxy lower alkyl group,

(lvii) a phenylamino group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group and a halogen substituted lower alkoxy group on the phenyl group,

(lviii) a phenyl lower alkenyl group,

(lix) a pyridylamino group that may have 1 to 3 lower alkyl groups,

(lx) a phenyl lower alkyl group (that may have as a substituent(s) on the phenyl group and/or the lower alkyl group 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, carbamoyl group and a lower alkoxycarbonyl group),

(lxi) a lower alkynyl group,

(lxii) a phenyloxy lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, N-lower alkoxy-N-lower alkylcarbamoyl group and oxopyrrolidinyl group as a substituent(s) on the phenyl group),

(lxiii) an isoxazolidinyl group that may have a single oxo group,

(lxiv) a dihydroindenyl group,

(lxv) a phenyl lower alkoxy lower alkyl group,

(lxvi) a tetrahydropyranyl group,

(lxvii) an azetidinyl group that may have 1 to 3 groups selected from the group consisting of a lower alkanoyl group and benzoyl group,

(lxviii) an azetidinyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkanoyl group and benzoyl group,

(lxix) a tetrazolyl group,

(lxx) an indolinyl group that may have a single oxo group,

(lxxi) a triazolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a lower alkylthio group,

(lxxii) an imidazolyl group that may have 1 to 3 carbamoyl groups,

(lxxiii) an oxazolyl group that may have 1 to 3 lower alkyl groups,

(lxxiv) an isothiazolyl group that may have 1 to 3 lower alkyl groups,

(lxxv) a benzimidazolyl group,

(lxxvi) a dihydrobenzothiazolyl group that may have a single oxo group,

(lxxvii) a thienyl group that may have 1 to 3 lower alkoxycarbonyl groups, and

(lxxviii) an oxazolyl lower alkyl group that may have 1 to 3 lower alkyl groups,

(29) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a benzoyl group and an amino substituted alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the amino group), on the amino group,

(30) a lower alkyl group substituted with a single carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group,

(31) a thiocarbamoyl group that may have 1 to 2 lower alkyl groups,

(32) a sulfamoyl group,

(33) an oxazolidinyl group that may have a single oxo group,

(34) an imidazolidinyl group that may have 1 to 2 substituents selected from the group consisting of an oxo group and a lower alkyl group,

(35) a pyrrolidinyl group that may have a single oxo group,

(36) an imidazolyl group,

(37) a triazolyl group,

(38) an isoxazolyl group,

(39) a piperidyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkylphenylsulfonyl group, an oxo group, a hydroxy group, and an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group and a lower alkanoylamino lower alkanoyl group,

(40) a piperidylcarbonyl group that may have 1 to 3 substituent(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group and a benzoyl group may be present), a piperidyl group (on which 1 to 3 groups selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group and a benzoyl group may be present), a piperazinyl group (on which 1 to 3 lower alkyl groups may be present as a substituent(s)), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepynyl group (on which a single lower alkyl group may be present as a substituent), a pyridyl group, a pyridyloxy group, a pyridyl lower alkoxy group, a tetrahydroquinolyl group (on which a single oxo group may be present), a benzodioxolyl group, a phenyl lower alkoxy group (that may have on the phenyl group 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkoxy group), a phenyl group (on which 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group and a hydroxy group may be present), phenyloxy group (that may have on the phenyl group 1 to 3 groups selected from the group consisting of a cyano group, a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkyl group), a phenyl lower alkyl group (on the phenyl group, 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkyl group may be present), and a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl group),

(41) a pyrrolidinylcarbonyl group that may have 1 to 3 groups as a substituent(s) selected from the group consisting of a hydroxy lower alkyl group, carbamoyl group, a hydroxy group, an amino group (that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group and a bemzoyl group on the amino group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a single lower alkyl group as a substituent on the piperazinyl group), an amino lower alkyl group (that may have 1 to 2 lower alkyl groups may be present as a substituent on the amino group), phenyloxy group (that may have 1 to 3 halogen substituted lower alkoxy groups on the phenyl group), a phenyloxy lower alkyl group (that may have 1 to 3 halogen substituted lower alkoxy groups on the phenyl group) and a tetrahydroquinolyl group (on which an oxo group may be present),

(42) a piperazinylcarbonyl group that may have 1 to 3 groups as a substituent(s) selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the amino group), a piperidyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxoranyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have 1 to 2 phenyl groups as a substituent(s) on the lower alkyl group), an imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group that may have 1 to 2 lower alkyl groups as a substituent(s)), a pyridyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a cyano group and a halogen substituted lower alkyl group as a substituent(s) on the pyridyl group), a thieno[2,3-b]pyridyl group, a phenyl group (on which 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group may be present), a benzoyl group, a furyl carbonyl group, a phenyl lower alkoxycarbonyl group and an oxo group,

(43) a hexahydroazepinylcarbonyl group,

(44) a hexahydro-1,4-diazepinylcarbonyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group and a pyridyl group,

(45) a dihydropyrrolylcarbonyl group that may have 1 to 3 lower alkyl groups,

(46) a thiomorpholinylcarbonyl group,

(47) a morpholinylcarbonyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group and a phenyl group,

(48) a thiazolidinyl carbonyl group that may have 1 to 3 phenyl groups that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a cyano group,

(49) an azabicyclo[3.2.2]nonylcarbonyl group,

(50) an 8-azabicyclo[3.2.1]octylcarbonyl group that may have 1 to 3 halogen substituted or unsubstituted phenyloxy groups,

(51) an indolinylcarbonyl group,

(52) a tetrahydroquinolylcarbonyl group,

(53) a tetrahydropyrido[3.4-b]indolylcarbonyl group,

(54) a morpholinyl lower alkyl group,

(55) a piperazinyl lower alkyl group that may have 1 to 3 lower alkyl groups on the piperazinyl group,

(56) a morpholinylcarbonyl lower alkyl group,

(57) a piperazinylcarbonyl lower alkyl group that may have 1 to 3 lower alkyl groups on the piperazinyl group,

(58) an oxo group,

(59) an amino lower alkoxy group (that may have 1 to 2 lower alkyl groups on the amino group),

(60) a lower alkoxy lower alkoxy group,

(61) a piperazinyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group and a lower alkoxycarbonyl group,

(62) a morpholinyl group,

(63) a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have 1 to 3 groups selected from the group consisting of an oxo group and a phenyl group,

(64) a tetrahydropyridylcarbonyl group that may have 1 to 3 pyridyl groups,

(65) an imidazolidinylcarbonyl group that may have a single thioxo group, and

(66) a 1,4-dioxa-8-azaspiro[4.5]decanyl group.

The present invention provides a compound represented by the general formula (1), wherein A is a lower alkylene group.

The present invention provides a compound represented by the general formula (1), wherein R¹ represents a cyclo C5-C6 alkyl group, an aromatic group or a heterocyclic group selected from the group consisting of (I) to (III) shown below:

(I) a cyclo C5-C6 alkyl group;

(II) a phenyl group; and

(III) a saturated or unsaturated heteromonocyclic group having 1 to 2 nitrogen atoms selected from the group consisting of a pyrrolidinyl group, a piperidyl group, a pyrazolyl group, a pyridyl group, pyrimidinyl group and a thiazolyl group, and

on the cyclo C5-C6 alkyl group, the aromatic group and the heterocyclic group represented by R¹, 1 to 5 groups selected from the group consisting of (1) to (66) defined in claim 2 may be present as a substituent(s).

The present invention provides a compound represented by the general formula (1), wherein R¹ represents (I) a cyclo C5-C6 alkyl group, and, on the cyclo C5-C6 alkyl group represented by R¹, 1 to 5 groups selected from the group consisting of (1) to (66) defined in claim 2 may be present as a substituent(s).

The present invention provides a compound represented by the general formula (1), wherein R¹ represents (II) a phenyl group, and, on aromatic group represented by R¹, 1 to 5 groups selected from the group consisting of (1) to (66) defined in claim 2 may be present as a substituent(s).

The present invention provides a compound represented by the general formula (1), wherein R¹ represents (III) a saturated or unsaturated heteromonocyclic group having 1 to 2 nitrogen atoms selected from a pyrrolidinyl group, a piperidyl group, pyrazolyl group, a pyridyl group, a pyrimidinyl group and a thiazolyl group, and, on heterocyclic group represented by R¹, 1 to 5 groups selected from the group consisting of (1) to (66) defined in claim 2 may be present as a substituent(s).

The present invention provides a compound represented by the general formula (1), wherein R¹ represents a cyclo C5-C6 alkyl group, an aromatic group or a heterocyclic group selected from the group consisting of (I) to (III) shown below:

(I) a cyclo C5-C6 alkyl group;

(II) a phenyl group; and

(III) a saturated or unsaturated heteromonocyclic group having 1 to 2 nitrogen atoms selected from a pyrrolidinyl group, a piperidyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group and a thiazolyl group, and

on the cyclo C5-C6 alkyl group, aromatic group and heterocyclic group represented by R¹, 1 to 5 groups selected from the group consisting of (1), (4), (10), (17), (18), (21), (28), (29), (30), (33), (34), (35), (36), (39), (61) and (62) shown below may be present as a substituent(s):

(1) a lower alkyl group,

(4) a lower alkoxy group,

(10) a hydroxy lower alkyl group,

(17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group and a lower alkoxycarbonylamino lower alkanoyl group, as a substituent(s),

(18) a lower alkanoyl group,

(21) a lower alkoxycarbonyl group,

(28) a carbamoyl group that may have 1 to 2 groups selected from the group consisting of the groups (i), (ii), (iv), (xii) and (xxi) below as a substituent(s):

(i) a lower alkyl group,

(ii) a lower alkoxy group,

(iv) a lower alkoxy lower alkyl group,

(xii) a lower alkyl group having 1 to 2 lower alkoxy carbonyl groups,

(xxi) a pyridyl lower alkyl group,

(29) an amino lower alkyl group that may have, on the amino group, 1 to 2 groups selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a benzoyl group and an amino substituted lower alkyl group (which may have 1 to 2 lower alkyl groups may be present as a substituent(s) on the amino group),

(30) a lower alkyl group substituted with a single carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group,

(33) an oxazolidinyl group that may have a single oxo group,

(34) an imidazolidinyl group that may have 1 to 2 substituents selected from the group consisting of an oxo group and a lower alkyl group,

(35) a pyrrolidinyl group that may have a single oxo group,

(36) an imidazolyl group,

(39) a piperidyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkyl phenylsulfonyl group, an oxo group, hydroxy group, and an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group and a lower alkanoylamino lower alkanoyl group,

(61) a piperazinyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group and a lower alkoxycarbonyl group, and

(62) a morpholinyl group.

The present invention provides a compound represented by the general formula (1), wherein R¹ represents (I) a cyclohexyl group, and, on the cyclo C5-C6 alkyl group represented by R¹, 1 to 3 groups selected from the group consisting of (1), (4), (10), (17), (18), (21), (28), (29), (30), (33), (34), (35), (36), (39), (61) and (62) defined in claim 8 may be present as a substituent(s).

The present invention provides a compound represented by the general formula (1), wherein R¹ represents (II) a phenyl group, and, on the aromatic group represented by R¹, 1 to 3 groups selected from the group consisting of (1), (4), (10), (17), (18) (21), (28), (29), (30), (33), (34), (35), (36), (39), (61) and (62) defined in claim 8 may be present as a substituent(s).

The present invention provides a compound represented by the general formula (1), wherein R¹ represents (II) a phenyl group, and, on the aromatic group represented by R¹, 1 to 3 groups selected from the group consisting of (1), (4), (10), (17), (18), (28), (33), (35), (39) and (61) shown below may be present as a substituent(s).

(1) a lower alkyl group,

(4) a lower alkoxy group,

(10) a hydroxy lower alkyl group,

(17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group and a lower alkoxy carbonylamino lower alkanoyl group, as a substituent(s),

(18) a lower alkanoyl group,

(28) a carbamoyl group having a single lower alkoxy lower alkyl group,

(33) an oxazolidinyl group that may have a single oxo group,

(35) a pyrrolidinyl group that may have a single oxo group,

(39) a piperidyl group, and

(61) a piperazinyl group that may have 1 to 2 groups selected from the group consisting of an oxo group, a lower alkanoyl group and a lower alkoxycarbonyl group.

The compound according to claim 11, wherein R¹ is a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single amino group having 1 or 2 lower alkyl groups on the amino group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single carbamoyl group having a single lower alkyl group, which has two lower alkoxy groups on the lower alkyl group;

a phenyl group having, on the phenyl group, a single hydroxy lower alkyl group, a single lower alkoxy group and a single oxazolidinyl group having a single oxo group on the oxazolidinyl group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single pyrrolidinyl group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single piperidyl group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single piperazyl group having a single lower alkanoyl group on the piperazyl group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single piperazyl group having a single lower alkanoyl group and a single oxo group on the piperazyl group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single piperazyl group having a single lower alkoxycarbonyl group and a single oxo group on the piperazyl group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single N—[(N-lower alkoxy-carbonylamino)lower alkanoyl]amino group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single N-(amino lower alkanoyl)amino group;

a phenyl group having, on the phenyl group, a single lower alkyl group, a single lower alkoxy group and a single N—[(N-lower alkanoyl amino)lower alkanoyl]amino group;

a phenyl group having, on the phenyl group, a single lower alkoxy group, a single lower alkanoyl group and a single piperazyl group having a single lower alkoxycarbonyl group on the piperazyl group; or

a phenyl group having, on the phenyl group, a single lower alkoxy group, a single hydroxy lower alkyl group and a single piperazyl group having a single lower alkoxycarbonyl group on the piperazyl group.

The present invention provides a compound represented by the general formula (1), wherein R¹ represents a saturated or unsaturated heteromonocyclic group having 1 to 2 nitrogen atoms selected from a piperidyl group, pyrazolyl group and thiazolyl group, and, on the heterocyclic group represented by R¹, 1 to 3 groups selected from the group consisting of (1), (4), (10), (17), (18), (21), (28), (29), (30), (33), (34), (35), (36), (39), (61) and (62) defined in claim 8 may be present as a substituent(s).

The present invention provides a compound represented by the general formula (1), wherein R¹ represents (III) a saturated or unsaturated heteromonocyclic group having 1 to 2 nitrogen atoms selected from a piperidyl group, pyrazolyl group and thiazolyl group, and, on the heterocyclic group represented by R¹, 1 to 3 groups selected from the group consisting of (1), (17) and (28) shown below may be present as a substituent(s).

(1) a lower alkyl group;

(17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group and a lower alkanoyl group, as a substituent(s); and

(28) a carbamoyl group that may have 1 to 2 lower alkyl groups.

The present invention provides a compound represented by the general formula (1), wherein R¹ represents

a pyrazolyl group having a single lower alkyl group and a single lower alkanoyl amino group;

a pyrazolyl group having a single lower alkyl group and a single N,N-di-lower alkyl amino group;

a piperidyl group having a single N,N-di-lower alkyl carbamoyl group; or

a thiazolyl group having a single N,N-di-lower alkyl carbamoyl group.

The present invention provides a pharmaceutical composition comprising a heterocyclic compound of the general formula (1) or a salt thereof according to the present invention, as an active ingredient and a pharmaceutically acceptable carrier.

The present invention provides a pharmaceutical composition according to the present invention can be used as a pharmaceutical composition for treating or preventing central nervous system disorders.

The present invention provides a pharmaceutical composition according to the present invention can be used as a pharmaceutical composition for treating or preventing central nervous system disorders selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type disorder; depression; endogenous; depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia; iatrogenic anhedonia; anhedonia of a psychic or mental cause; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache); mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.

The present invention provides a process for producing a pharmaceutical composition comprising mixing a heterocyclic compound represented by the formula (1) or a salt thereof with a pharmaceutically acceptable carrier.

The present invention provides use of a heterocyclic compound represented by the formula (1) or a salt thereof as a drug.

Specifically provided is of a heterocyclic compound represented by the formula (1) or a salt thereof, as a dopamine D₂ receptor partial agonist and/or serotonin 5-HT_(2A) receptor antagonist and/or an adrenaline α₁ receptor antagonist and/or a serotonin uptake inhibitor (or a serotonin reuptake inhibitor).

The present invention provides a method for treating or preventing a central nervous system disorder comprising administering a heterocyclic compound of the formula (1) or a salt thereof to human or animal.

The present invention provides a process for producing a heterocyclic compound represented by the formula (1):

[wherein R₁, R₂ and A are the same as defined in claim 1] or a salt thereof, characterized by comprising a reaction of a compound represented by the formula: R₁—O-A-X₁ [wherein R₁ and A are the same as defined above, and X₁ represents a halogen atom or a group which causes a substitution reaction the same as in a halogen atom] or a salt thereof with a compound represented by the formula:

[wherein R₂ is the same as defined above] or a salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

Specific examples of each of the groups shown in the general formula (1) are as follows.

Specific examples of each of the groups shown in the general formula are as follows.

Examples of the lower alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1-ethylpropyl group, isopentyl group, neo-pentyl group, n-hexyl group, 1,2,2-trimethylpropyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group, isohexyl group, and 3-methylpentyl group.

Examples of the lower alkylene group include a linear or branched alkylene group having 1 to 6 carbon atoms. Specific examples thereof include a methylene group, ethylene group, trimethylene group, 2-methyltrimethylene group, 2,2-dimethylethylene group, 2,2-dimethyltrimethylene group, 1-methyltrimethylene group, methylmethylene group, ethylmethylene group, tetramethylene group, pentamethylene group, and hexamethylene group.

Examples of the lower alkenylene group include a linear or branched alkenylene group having 1 to 3 double bonds and 2 to 6 carbon atoms. Specific examples thereof include a vinylene group, 1-propenylene group, 1-methyl-1-propenylene group, 2-methyl-1-propenylene group, 2-propenylene group, 2-butenylene group, 1-butenylene group, 3-butenylene group, 2-pentenylene group, 1-pentenylene group, 3-pentenylene group, 4-pentenylene group, 1,3-butadienylene group, 1,3-pentadienylene group, 2-penten-4-ynylene group, 2-hexenylene group, 1-hexenylene group, 5-hexenylene group, 3-hexenylene group, 4-hexenylene group, 3,3-dimethyl-1-propenylene group, 2-ethyl-1-propenylene group, 1,3,5-hexatrienylene group, 1,3-hexadienylene group, and 1,4-hexadienylene group.

Examples of the lower alkenyl group include a linear or branched alkenyl group having 1 to 3 double bonds and 2 to 6 carbon atoms, including both a trans and cis-configurations. Specific examples thereof include a vinyl group, 1-propenyl group, 2-propenyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 2-propenyl group, 2-butenyl group, 1-butenyl group, 3-butenyl group, 2-pentenyl group, 1-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,3-butadienyl group, 1,3-pentadienyl group, 2-penten-4-yl group, 2-hexenyl group, 1-hexenyl group, 5-hexenyl group, 3-hexenyl group, 4-hexenyl group, 3,3-dimethyl-1-propenyl group, 2-ethyl-1-propenyl group, 1,3,5-hexatrienyl group, 1,3-hexadienyl group, and 1,4-hexadienyl group.

Examples of the halogen atom include a fluorine atom, chlorine atom, bromine atom and iodine atom.

Examples of the halogen substituted lower alkyl group include a lower alkyl group as illustrated above substituted with 1 to 7, more preferably, 1 to 3 halogen atoms. Specific examples thereof include a fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, dichlorofluoromethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, 3,3,3-trifluoropropyl group, heptafluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, heptafluoroisopropyl group, 3-chloropropyl group, 2-chloropropyl group, 3-bromopropyl group, 4,4,4-trifluorobutyl group, 4,4,4,3,3-pentafluorobutyl group, 4-chlorobutyl group, 4-bromobutyl group, 2-chlorobutyl group, 5,5,5-trifluoropentyl group, 5-chloropentyl group, 6,6,6-trifluorohexyl group, 6-chlorohexyl group, and perfluorohexyl group.

Examples of the lower alkoxy group include a linear or branched alkoxy group having 1 to 6 carbon atoms. Specific examples thereof include a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, and 3-methylpentyloxy group.

Examples of the aryl group include a phenyl group, substituted phenyl group, biphenyl group, substituted biphenyl group, naphthyl group, and substituted naphthyl group. Examples of the substituent for an aryl group include a lower alkyl group as illustrated above (preferably a linear or branched lower alkyl group having 1 to 6 carbon atoms), a halogen atom as illustrated above, and an amino group. On the aryl group, 1 to 7, preferably 1 to 5, more preferably, 1 to 2 substituents of at least one type of these may be present. Specific examples of the aryl group may include a phenyl group, (2-, 3-, or 4-) biphenyl group, (1- or 2-)naphthyl group, (2-, 3-, or 4-)methylphenyl group, (2-, 3-, or 4-)ethylphenyl group, (2-, 3-, or 4-)n-propylphenyl group, (2-, 3-, or 4-)n-butylphenyl group, (2-, 3-, or 4-)n-pentylphenyl group, (2-, 3-, or 4-)n-hexylphenyl group, (2-, 3-, or 4-)isobutylphenyl group, (2-, 3-, or 4-)tert-butylphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-4-biphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-4-biphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-4-biphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-4-biphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-4-biphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-4-biphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-4-biphenyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-2-biphenyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-3-biphenyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-4-biphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-2-naphthyl group, (2-, 3-, or 4-)chlorophenyl group, (2-, 3-, or 4-)fluorophenyl group, (2-, 3-, or 4-)bromophenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-2-naphthyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-2-naphthyl group, (2-, 3-, or 4-)aminophenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-1-naphthyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-2-naphthyl group, 2,3-dimethylphenyl group, 3,4-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6-dimethylphenyl group, 2,4,6-trimethylphenyl group, 3,4,5-trimethylphenyl group, 2,3,4,5-tetraethylphenyl group, pentamethylphenyl group, 2,4-dimethyl-1-naphthyl group, 2,3-dimethyl-1-naphthyl group, 3,4-dimethyl-1-naphthyl group, 3,5,7-triethylnaphthyl group, 3,4,5,7-tetramethyl-1-naphthyl group, 2,3,4,5,7-pentamethyl-1-naphthyl group, 2,3,4,5,6,7-hexaethyl-1-naphthyl group, heptamethyl-1-naphthyl group, 2,3-diaminophenyl group, 2,4,6-triaminophenyl group, and 2-methyl-5-chloro-1-naphthyl group.

Examples of the aryloxy group include a phenyloxy group, substituted phenyloxy group, biphenyloxy group, substituted biphenyloxy group, naphthyloxy group, and substituted naphthyloxy group. Examples of the substituent for an aryloxy group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms), a halogen atom as illustrated above, and an amino group. On the aryl group, 1 to 7, preferably 1 to 5, more preferably, 1 to 2 substituents of at least one type of these may be present. Specific examples of the aryloxy groups include a phenyloxy group, (2-, 3-, or 4-)biphenyloxy group, (1- or 2-)naphthyloxy group, (2-, 3-, or 4-)methylphenyloxy group, (2-, 3-, or 4-)ethylphenyloxy group, (2-, 3-, or 4-)n-propylphenyloxy group, (2-, 3-, or 4-)n-butylphenyloxy group, (2-, 3-, or 4-)n-pentylphenyloxy group, (2-, 3-, or 4-)n-hexylphenyloxy group, (2-, 3-, or 4-)isobutylphenyloxy group, (2-, 3-, or 4-)tert-butylphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-4-biphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-4-biphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-4-biphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-4-biphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-4-biphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-4-biphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-4-biphenyloxy group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-2-biphenyloxy group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-3-biphenyloxy group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-4-biphenyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-2-naphthyloxy group, (2-, 3-, or 4-)chlorophenyloxy group, (2-, 3-, or 4-)fluorophenyloxy group, (2-, 3-, or 4-)bromophenyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-2-naphthyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-2-naphthyloxy group, (2-, 3-, or 4-)aminophenyloxy group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-1-naphthyloxy group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-2-naphthyloxy group, 2,3-dimethylphenyloxy group, 3,4-dimethylphenyloxy group, 2,4-dimethylphenyloxy group, 2,5-dimethylphenyloxy group, 2,6-dimethylphenyloxy group, 2,4,6-trimethylphenyloxy group, 3,4,5-trimethylphenyloxy group, 2,3,4,5-tetraethylphenyloxy group, pentamethylphenyloxy group, 2,4-dimethyl-1-naphthyloxy group, 2,3-dimethyl-1-naphthyloxy group, 3,4-dimethyl-1-naphthyloxy group, 3,5,7-triethyl-1-naphthyloxy group, 3,4,5,7-tetramethyl-1-naphthyloxy group, 2,3,4,5,7-pentamethyl-1-naphthyloxy group, 2,3,4,5,6,7-hexaethyl-1-naphthyloxy group, heptamethyl-1-naphthyloxy group, 2,3-diaminophenyloxy group, 2,4,6-triaminophenyloxy group, and 2-methyl-5-chloro-1-naphthyloxy group.

Examples of the lower alkylthio group include a linear or branched alkylthio group having 1 to 6 carbon atoms. Specific examples thereof include a methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, tert-butylthio group, n-pentylthio group, and n-hexylthio group.

Examples of the halogen-substituted lower alkoxy group include a lower alkoxy group as illustrated above substituted with 1 to 7, preferably, 1 to 3 halogen atoms. Specific examples thereof include a fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chloromethoxy group, dichloromethoxy group, trichloromethoxy group, bromomethoxy group, dibromomethoxy group, dichlorofluoromethoxy group, 2,2,2-trifluoroethoxy group, pentafluoroethoxy group, 2-chloroethoxy group, 3,3,3-trifluoropropoxy group, heptafluoropropoxy group, heptafluoroisopropoxy group, 3-chloropropoxy group, 2-chloropropoxy group, 3-bromopropoxy group, 4,4,4-trifluorobutoxy group, 4,4,4,3,3-pentafluorobutoxy group, 4-chlorobutoxy group, 4-bromobutoxy group, 2-chlorobutoxy group, 5,5,5-trifluoropentoxy group, 5-chloropentoxy group, 6,6,6-trifluorohexyloxy group, and 6-chlorohexyloxy group.

Examples of the protecting group of a hydroxy group include a linear or branched alkyl group having 1 to 6 carbon atoms, a lower alkanoyl group (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms), and a phenyl lower alkyl group whose lower alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the hydroxy group protected include a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, n-hexyloxy group, isohexyloxy group, 3-methylpentyloxy group, lower alkanoyloxy group and phenyl lower alkoxy group. Specific examples include a formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, pentanoyloxy group, tert-butylcarbonyloxy group, hexanoyloxy group, benzyloxy group, 2-phenylethoxy group, 1-phenylethoxy group, 3-phenylpropoxy group, 4-phenylbutoxy group, 5-phenylpentyloxy group, 6-phenylhexyloxy group, 1,1-dimethyl-2-phenylethoxy group, and 2-methyl-3-phenylpropoxy group.

Examples of the hydroxy lower alkyl group include a lower alkyl group as illustrated above having 1 to 5, preferably 1 to 3 hydroxy groups (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2,3-dihydroxypropyl group, 4-hydroxybutyl group, 3,4-dihydroxybutyl group, 1,1-dimethyl-2-hydroxyethyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 3,3-dimethyl-3-hydroxypropyl group, 2-methyl-3-hydroxypropyl group, 2,3,4-trihydroxybutyl group, and perhydroxyhexyl group.

Example of a protecting group of a hydroxy lower alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms, a lower alkanoyl group (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms), and a phenyl lower alkyl group whose lower alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the hydroxy lower alkyl group protected include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 5, preferably 1 to 3 protected hydroxy groups as illustrated above (preferably a lower alkoxy group, lower alkanoyloxy group or phenyl lower alkoxy group). Specific examples thereof include a methoxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2-n-propoxyethyl group, 2-isopropoxyethyl group, 2-n-butoxyethyl group, 2-isobutoxyethyl group, 2-tert-butoxyethyl group, 2-sec-butoxyethyl group, 2-n-pentyloxyethyl group, 2-isopentyloxyethyl group, 2-neopentyloxyethyl group, 2-n-hexyloxyethyl group, 2-isohexyloxyethyl group, 2-(3-methylpentyloxy)ethyl group, 2-formyloxyethyl group, 2-acetyloxyethyl group, 2-propionyloxyethyl group, 2-butyryloxyethyl group, 2-isobutyryloxyethyl group, 2-pentanoyloxyethyl group, 2-tert-butylcarbonyloxyethyl group, 2-hexanoyloxyethyl group, 2-benzyloxyethyl group, 2-(2-phenylethoxy)ethyl group, 2-(1-phenylethoxy)ethyl group, 2-(3-phenylpropoxy)ethyl group, 2-(4-phenylbutoxy)ethyl group, 2-(5-phenylpentyloxy)ethyl group, 2-(6-phenylhexyloxy)ethyl group, 2-(1,1-dimethyl-2-phenylethoxy)ethyl group, 2-(2-methyl-3-phenylpropoxy)ethyl group, 3-ethoxypropyl group, 2,3-diethoxypropyl group, 4-ethoxybutyl group, 3,4-diethoxybutyl group, 1,1-dimethyl-2-ethoxyethyl group, 5-ethoxypentyl group, 6-ethoxyhexyl group, 3,3-dimethyl-3-ethoxypropyl group, 2-methyl-3-ethoxypropyl group, and 2,3,4-triethoxybutyl group.

Examples of the lower alkanoyl group include a linear or branched alkanoyl group having 1 to 6 carbon atoms. Specific examples thereof include a formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group, tert-butylcarbonyl group, and hexanoyl group.

Examples of the lower alkoxycarbonyl group include a linear or branched alkoxycarbonyl group whose lower alkoxy moiety is one as illustrated above, and preferably having 1 to 6 carbon atoms. Specific examples thereof include a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxy carbonyl group, tert-butoxycarbonyl group, sec-butoxycarbonyl group, n-pentyloxycarbonyl group, neopentyloxy group, n-hexyloxycarbonyl group, isohexyloxycarbonyl group, and 3-methylpentyloxycarbonyl group.

Examples of the lower alkylsulfonyl group include a linear or branched alkylsulfonyl group whose lower alkyl moiety is one as illustrated above, and preferably having 1 to 6 carbon atoms. Specific examples thereof include a methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, tert-butylsulfonyl group, sec-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, n-hexylsulfonyl group, isohexylsulfonyl group, and 3-methylpentylsulfonyl group.

Examples of the lower alkylcarbamoyl group include a carbamoyl group having 1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) as a substituent(s). Specific examples thereof include a N-methylcarbamoyl group, N,N-dimethylcarbamoyl group, N-ethylcarbamoyl group, N,N-diethylcarbamoyl group, N-n-propylcarbamoyl group, N-n-butylcarbamoyl group, N-n-pentylcarbamoyl group, N-n-hexylcarbamoyl group, N-isobutylcarbamoyl group, N-tert-butylcarbamoyl group, and N,N-di-n-propylcarbamoyl group.

Examples of the aminoalkanoyl group include a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms) having 1 to 3 (preferably 1) amino groups. Specific examples thereof include an aminoacetyl group, 3-aminopropionyl group, 4-aminobutyryl group, 3,4-diaminobutyryl group, 3,3-dimethyl-3-aminopropionyl group, 4-aminobutyryl group and 5-aminovaleryl group.

Examples of the lower alkanoyl amino lower alkanoyl group include a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms) whose lower alkanoyl moiety has 1 to 3 (preferably 1) lower alkanoylamino groups as illustrated above. Specific examples thereof include an N-formylaminoacetyl group, N-acetylaminoacetyl group, N-propionylaminoacetyl group, 3-(N-acetylamino)propionyl group, 4-(N-acetylamino)butyryl group, 3,4-di(N-acetylamino)butyryl group, 3,3-dimethyl-3-(N-propinylamino)propionyl group, 4-(N-formylamino)butyryl group, and 5-(N-acetylamino)valeryl group.

Examples of the lower alkoxy carbonylamino lower alkanoyl group include a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms) whose lower alkoxycarbonyl moiety has 1 to 3 (preferably 1) lower alkoxy carbonylamino groups as illustrated above. Specific examples thereof include an N-methoxycarbonylaminoacetyl group, N-ethoxycarbonylaminoacetyl group, N-tert-butoxycarbonylaminoacetyl group, 3-(N-methoxycarbonylamino)propionyl group, 4-(N-acetylamino)butyryl group, 3,4-di(N-acetylamino)butyryl group, 3,3-dimethyl-3-(N-propinylamino)propionyl group, 4-(N-formylamino)butyryl group and 5-(N-acetylamino)valeryl group. Examples of the amino group having, as a substituent, a group selected from the group consisting of a lower alkyl group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfonyl group, carbamoyl group, lower alkylcarbamoyl group, amino lower alkanoyl group, lower alkanoylamino lower alkanoyl group, and lower alkoxycarbonylamino lower alkanoyl group include an amino group having, as a substituent, 1 to 2 groups selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms);

a lower alkoxycarbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms);

a lower alkylsulfonyl group as illustrated above (preferably a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms);

a carbamoyl group;

a lower alkylcarbamoyl group as illustrated above (preferably a carbamoyl group having, as a substituent, 1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms)); an amino lower alkanoyl group as illustrated above; a lower alkanoylamino lower alkanoyl group as illustrated above; and a lower alkoxycarbonylamino lower alkanoyl group as illustrated above. Specific examples thereof include an amino group, N-methylamino group, N,N-dimethylamino group, N-ethylamino group, N-n-propylamino group, N-isopropylamino group, N-formylamino group, N-acetylamino group, N-tert-butoxycarbonylamino group, N-methoxycarbonylamino group, N-methylsulfonylamino group, N-ethylsulfonylamino group, N-methyl-N-acetylamino group, N-methyl-N-methoxycarbonylamino group, N—[N,N-dimethylcarbamoyl]amino group, N-carbamoylamino group, N—[N-methylcarbamoyl]amino group, N—[N,N-diethylcarbamoyl]amino group, N—[aminoacetyl]amino group, N—[[N-formylamino]acetyl]amino group, N—[[N-acetylamino]acetyl]amino group, N—[[N-methoxycarbonylamino]acetyl]amino group, and N—[[N-tert-butoxycarbonylamino]acetyl]amino group.

Examples of the arylsulfonyl group that may have a lower alkyl group on an aryl group include an arylsulfonyl group whose aryl moiety is phenyl, biphenyl, naphthyl or the like and on which 1 to 7, preferably 1 to 5, more preferably, 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms. Specific examples of the arylsulfonyl group that may have a lower alkyl group on an aryl group include a phenylsulfonyl group, (2-, 3-, or 4-)biphenylsulfonyl group, (1- or 2-)naphthylsulfonyl group, (2-, 3-, or 4-)methylphenylsulfonyl group, (2-, 3-, or 4-)ethylphenylsulfonyl group, (2-, 3-, or 4-)n-propylphenylsulfonyl group, (2-, 3-, or 4-)n-butylphenylsulfonyl group, (2-, 3-, or 4-)n-pentylphenylsulfonyl group, (2-, 3-, or 4-)n-hexylphenylsulfonyl group, (2-, 3-, or 4-)isobutylphenylsulfonyl group, (2-, 3-, or 4-)tert-butylphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-4-biphenylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-) methyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-2-naphthylsulfonyl group, 2,3-dimethylphenylsulfonyl group, 3,4-dimethylphenylsulfonyl group, 2,4-dimethylphenylsulfonyl group, 2,5-dimethylphenylsulfonyl group, 2,6-dimethylphenylsulfonyl group, 2,4,6-trimethylphenylsulfonyl group, 3,4,5-trimethylphenylsulfonyl group, 2,3,4,5-tetraethylphenylsulfonyl group, pentamethylphenylsulfonyl group, 2,4-dimethyl-1-naphthylsulfonyl group, 2,3-dimethyl-1-naphthylsulfonyl group, 3,4-dimethyl-1-naphthylsulfonyl group, 3,5,7-triethyl-1-naphthylsulfonyl group, 3,4,5,7-tetramethyl-1-naphthylsulfonyl group, 2,3,4,5,7-pentamethyl-1-naphthylsulfonyl group, 2,3,4,5,6,7-hexaethyl-1-naphthylsulfonyl group, and heptamethyl-1-naphthylsulfonyl group.

Examples of a carboxyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3 (preferably 1) carboxyl groups. Specific examples thereof include carboxymethyl group, 2-carboxyethyl group, 1-carboxyethyl group, 1-carboxy-1-methylethyl group, 3-carboxypropyl group, 2,3-dicarboxypropyl group, 4-carboxybutyl group, 3,4-dicarboxybutyl group, 1,1-dimethyl-2-carboxyethyl group, 5-carboxypentyl group, 6-carboxyhexyl group, 3,3-dimethyl-3-carboxypropyl group, 2-methyl-3-carboxypropyl group, and 2,3,4-tricarboxybutyl group.

Examples of a lower alkoxycarbonyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3 (preferably 1 to 2) lower alkoxycarbonyl groups as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms). Specific examples thereof include a methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 1-methoxycarbonylethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 1-ethoxycarbonylethyl group, 3-methoxycarbonylpropyl group, 3-ethoxycarbonylpropyl group, 4-ethoxycarbonylbutyl group, 5-isopropoxycarbonylpentyl group, 6-n-propoxycarbonylhexyl group, 1,1-dimethyl-2-n-butoxycarbonylethyl group, 1-methyl-1-methoxycarbonylethyl group, 2-methyl-1-methoxycarbonylpropyl group, 2-methyl-3-tert-butoxycarbonylpropyl group, 3-methyl-1-methoxycarbonylbutyl group, diethoxycarbonylmethyl group, 1,2-diethoxycarbonylethyl group, 2-n-pentyloxycarbonylethyl group, and n-hexyloxycarbonylmethyl group.

Examples of the carbamoyl lower alkyl group that may have a group, as a substituent, selected from the group consisting of a lower alkyl group, a phenyl group that may have a lower alkyl group and a phenyl group that may have a lower alkoxy group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3 (preferably 1 to 2) carbamoyl groups. The carbamoyl moiety may have 1 to 2 groups selected from the group consisting of a phenyl group that may have 1 to 3 (preferably 1) lower alkyl groups as illustrated above (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) and a phenyl group that may have 1 to 3 (preferably 1) lower alkoxy groups as illustrated above (preferably linear or branched alkoxy groups having 1 to 6 carbon atoms). Specific examples of the carbamoyl lower alkyl group include a carbamoylmethyl group, dicarbamoylmethyl group, 2-carbamoylethyl group, 1-carbamoylethyl group, 1-carbamoyl-2-methylpropyl group, 3-carbamoylpropyl group, 4-carbamoylbutyl group, 5-carbamoylpentyl group, 6-carbamoylhexyl group, 1,1-dimethyl-2-carbamoylethyl group, 2-methyl-3-carbamoylpropyl group, N-methylcarbamoylmethyl group, N,N-dimethylcarbamoylmethyl group, N-methyl-N-ethylcarbamoylmethyl group, N-methylcarbamoylmethyl group, 2-(N-methylcarbamoyl)ethyl group, 2-(N-ethylcarbamoyl)ethyl group, N-phenylcarbamoylmethyl group, N-(2-methoxyphenyl)carbamoylmethyl group, and N-(4-methylphenyl)carbamoylmethyl group.

Examples of the carboxyl lower alkenyl group include a lower alkenyl group as illustrated above having 1 to 3, preferably 1, carboxyl groups and including both trans and cis configurations (preferably a linear or branched alkenyl group having 1 to 3 double bonds and 2 to 6 carbon atoms). Specific examples thereof include a 2-carboxyethenyl group, 3-carboxy-2-propenyl group, 4-carboxy-2-butenyl group, 4-carboxy-3-butenyl group, 4-carboxy-1,3-butadienyl group, 5-carboxy-1,3,5-hexatrienyl group, 5-carboxy-2,4-hexadienyl group, 5-carboxy-3-pentenyl group, and 3-carboxy-1-propenyl group.

Examples of the lower alkoxycarbonyl lower alkenyl group include a lower alkenyl group as illustrated above (preferably a linear or branched alkenyl group having 1 to 3 double bonds and 2 to 6 carbon atoms) having 1 to 3 lower alkoxycarbonyl groups as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms) and including both trans and cis configurations. Specific example of the lower alkoxycarbonyl lower alkenyl group include a 2-methoxycarbonylethenyl group, 2-ethoxycarbonylethenyl group, 1-ethoxycarbonylethenyl group, 3-methoxycarbonyl-2-propenyl group, 3-ethoxycarbonyl-2-propenyl group, 4-ethoxycarbonyl-2-butenyl group, 4-ethoxycarbonyl-1,3-buthadienyl group, 5-isopropoxycarbonyl-3-pentenyl group, 6-n-propoxycarbonyl-1,3,5-hexatrienyl group, 1,1-dimethyl-2-n-butoxycarbonylethenyl group, 2-methyl-3-tert-butoxycarbonyl-2-propenyl group, and 2-n-pentyloxycarbonylethenyl group.

Examples of the carbamoyl lower alkenyl group include a lower alkenyl group as illustrated above (preferably a linear or branched alkenyl group having 2 to 6 carbon atoms and 1 to 3 double bonds) having 1 to 3, preferably 1, carbamoyl groups. Specific examples thereof include a 2-carbamoylethenyl group, 3-carbamoyl-2-propenyl group, 4-carbamoyl-2-butenyl group, 4-carbamoyl-3-butenyl group, 4-carbamoyl-1,3-butadienyl group, 5-carbamoyl-1,3,5-hexatrienyl group, 5-carbamoyl-2,4-hexadienyl group, 5-carbamoyl-3-pentenyl group, and 3-carbamoyl-1-propenyl group.

Examples of the carbamoyl lower alkenyl group that may have, as a substituent, a group selected from the group consisting of a lower alkyl group and a halogen-substituted lower alkyl group include a lower alkenyl group as illustrated above (preferably a linear or branched alkenyl group having 1 to 3 double bonds and 2 to 6 carbon atoms) having 1 to 3, preferably 1 carbamoyl group that may have, on the carbamoyl group, 1 to 2 substituents selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms); and

a halogen-substituted lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms having 1 to 7, preferably 1 to 3 substituents of halogen atoms). Specific examples thereof include a 2-carbamoylethenyl group, 2-(N-methylcarbamoyl)ethenyl group, 2-(N-ethylcarbamoyl)ethenyl group, 2-(N,N-dimethylcarbamoyl)ethenyl group, and 2-[N-(2,2,2-trifluoroethyl)carbamoyl]ethenyl group.

Examples of the lower alkoxy lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3, preferably 1, lower alkoxy groups as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms). Specific examples thereof include a methoxymethyl group, 2-methoxyethyl group, 1-ethoxyethyl group, 2-ethoxyethyl group, 2-isobutoxyethyl group, 2,2-dimethoxyethyl group, 2-methoxy-1-methylethyl group, 2-methoxy-1-ethylethyl group, 3-methoxypropyl group, 3-ethoxypropyl group, 2-isopropoxyethyl group, 3-isopropoxypropyl group, 3-n-butoxypropyl group, 4-n-propoxybutyl group, 1-methyl-3-isobutoxy propyl group, 1,1-dimethyl-2-n-pentyloxyethyl group, 5-n-hexyloxypentyl group, 6-methoxyhexyl group, 1-ethoxyisopropyl group, and 2-methyl-3-methoxypropyl group.

Examples of the aryloxy lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3, preferably 1 aryloxy groups whose aryl moiety is phenyl, biphenyl, naphthyl or the like. Examples of a substituent for an aryl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms), a halogen atom as illustrated above, and an amino group. One to seven substituents of at least one type of these may be present on an aryl ring. Specific examples of the aryloxy lower alkyl include a phenoxymethyl group, 2-phenoxyethyl group, 2-[(1- or 2-)naphthyloxy]ethyl group, 2-[(2-, 3-, or 4-)methylphenoxy]ethyl group, 2-[(2-, 3-, or 4-)ethylphenoxy]ethyl group, 2-[(2-, 3-, or 4-)n-propylphenoxy]ethyl group, 2-[(2-, 3-, or 4-)n-butylphenoxy]ethyl group, 2-[(2-, 3-, or 4-)n-pentylphenoxy]ethyl group, 2-[(2-, 3-, or 4-)n-hexylphenoxy]ethyl group, 2-[(2-, 3-, or 4-)isobutylphenoxy]ethyl group, 2-[(2-, 3-, or 4-)tert-butylphenoxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-2-naphthyloxy)ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-2-naphthyloxy]ethyl group, 2-[(2-, 3-, or 4-)chlorophenoxy]ethyl group, 2-[(2-, 3-, or 4-)fluorophenoxy]ethyl group, 2-[(2-, 3-, or 4-)bromophenoxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-2-naphthyloxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-2-naphthyloxy]ethyl group, 2-[(2-, 3-, or 4-)aminophenoxy]ethyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-1-naphthyloxy]ethyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-2-naphthyloxy]ethyl group, 2-(2,3-dimethylphenoxy)ethyl group, 2-(3,4-dimethylphenoxy)ethyl group, 2-(2,4-dimethylphenoxy)ethyl group, 2-(2,5-dimethylphenoxy)ethyl group, 2-(2,6-dimethylphenoxy)ethyl group, 2-(2,4,6-trimethylphenoxy)ethyl group, 2-(3,4,5-trimethylphenoxy)ethyl group, 2-(2,3,4,5-tetraethylphenoxy)ethyl group, 2-(pentamethylphenoxy)ethyl group, 2-(2,4-dimethyl-1-naphthyloxy)ethyl group, 2-(2,3-dimethyl-1-naphthyloxy)ethyl group, 2-(3,4-dimethyl-1-naphthyloxy)ethyl group, 2-(3,5,7-triethyl-1-naphthyloxy)ethyl group, 2-(3,4,5,7-tetramethyl-1-naphthyloxy)ethyl group, 2-(2,3,4,5,7-pentamethyl-1-naphthyloxy)ethyl group, 2-(2,3,4,5,6,7-hexaethyl-1-naphthyloxy)ethyl group, 2-(heptamethyl-1-naphthyloxy)ethyl group, 2-(2,3-diaminophenoxy)ethyl group, 2-(2,4,6-triaminophenoxy)ethyl group, 2-(2-methyl-5-chloro-1-naphthyl)ethyl group, 3-phenoxypropyl group, 2,3-diphenoxypropyl group, 4-phenoxybutyl group, 3,4-diphenoxybutyl group, 1,1-dimethyl-2-phenoxyethyl group, 5-phenoxypentyl group, 6-phenoxyhexyl group, 3,3-dimethyl-3-phenoxypropyl group, 2-methyl-3-phenoxypropyl group, and 2,3,4-triphenoxybutyl group, 3-[(1- or 2-)naphthyloxy]propyl group, 2,3-di[(1- or 2-)naphthyloxy]propyl group, 4-[(1- or 2-)naphthyloxy]butyl group, 3,4-di[(1- or 2-)naphthyloxy]butyl group, 1,1-dimethyl-2-[(1- or 2-)naphthyloxy]ethyl group, 5-[(1- or 2-)naphthyloxy]pentyl group, 6-[(1- or 2-)naphthyloxy]hexyl group, 3,3-dimethyl-3-[(1- or 2-)naphthyloxy]propyl group, 2-methyl-3-[(1- or 2-)naphthyloxy]propyl group, and 2,3,4-tri[(1- or 2-)naphthyloxy]butyl group.

Examples of the amino lower alkyl group that may have a group selected from the group consisting of a lower alkyl group, lower alkanoyl group, aroyl group and carbamoyl group include

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 5 (preferably 1) amino groups that may have 1 to 2 groups selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms), lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms), aroyl group as illustrated above (preferably benzoyl group) as illustrated above and carbamoyl group. Specific examples of the amino lower alkyl group include an aminomethyl group, 2-aminoethyl group, 1-aminoethyl group, 3-aminopropyl group, 4-aminobutyl group, 5-aminopentyl group, 6-aminohexyl group, 1,1-dimethyl-2-aminoethyl group, 2-methyl-3-aminopropyl group, N,N-dimethylaminomethyl group, N-methyl-N-ethylaminomethyl group, N-methylaminomethyl group, 2-(N-methylamino)ethyl group, 1-methyl-2-(N,N-dimethylamino)ethyl group, 1-methyl-2-(N,N-diethylamino)ethyl group, 2-(N,N-dimethylamino)ethyl group, 2-(N,N-diethylamino)ethyl group, 2-(N,N-diisopropylamino)ethyl group, 3-(N,N-dimethylamino)propyl group, 3-(N,N-diethylamino)propyl group, 2-(N-acetylamino)ethyl group, 2-(N-methyl-N-acetylamino)ethyl group, 2-(N-methyl-N-n-butyrylamino)ethyl group, 2-(N-methyl-N-benzoylamino)ethyl group, and 2-(N-carbamoylamino)ethyl group.

Examples of the cyclo C3-C8 alkyl group include a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group.

Examples of the cyclo C3-C8 alkyl group that may have a group, as a substituent, selected from the group consisting of a lower alkyl group, hydroxy group, lower alkoxy carbonyl group and phenyl lower alkoxy group include a cyclo C3-C8 alkyl group that may have 1 to 3 (preferably 1) groups, as a substituent(s), selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a hydroxy group;

a lower alkoxy carbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms); and

a lower alkoxy group (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms) having 1 to 3 (preferably 1) phenyl groups. Specific examples thereof include a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, 1-methylcyclopropyl group, 1-methylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group, 4-hydroxycyclohexyl group, 4-methoxycarbonylcyclohexyl group, 2-benzyloxypentyl group, and 2-benzyloxyhexyl group.

Example of the cyclo C3-C8 alkyl substituted lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3, preferably 1 cyclo C3-C8 alkyl group as illustrated above. Specific examples thereof include a cyclopropylmethyl group, cyclohexylmethyl group, 2-cyclopropylethyl group, 1-cyclobutylethyl group, cyclopentylmethyl group, 3-cyclopentylpropyl group, 4-cyclohexylbutyl group, 5-cycloheptylpentyl group, 6-cyclooctylhexyl group, 1,1-dimethyl-2-cyclohexylethyl group, and 2-methyl-3-cyclopropylpropyl group.

Examples of the furyl lower alkyl group (that may have a substituent of a lower alkyl group on the furyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) furyl groups on which 1 to 3 (preferably 1 to 2) lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present as a substituent. Specific examples thereof include a [(2- or 3-)furyl]methyl group, 2-[(2- or 3-) furyl]ethyl group, 1-[(2- or 3-)furyl]ethyl group, 3-[(2- or 3-)furyl]propyl group, 4-[(2- or 3-)furyl]butyl group, 5-[(2- or 3-)furyl]pentyl group, 6-[(2- or 3-)furyl]hexyl group, 1,1-dimethyl-2-[(2- or 3-)furyl]ethyl group, 2-methyl-3-[(2- or 3-)furyl]propyl group, [5-ethyl-(2-, 3-, or 4-)furyl]methyl group, [5-methyl-(2-, 3-, or 4-)furyl]methyl group, [2-n-propyl-(3-, 4-, or 5-)furyl]methyl group, [3-tert-butyl-(2-, 4-, or 5-)furyl]methyl group, [4-n-pentyl-(2-, 3-, or 5-)furyl]methyl group, [2-n-hexyl-(3-, 4-, or 5-)furyl]methyl group, [2,5-dimethyl-(3- or 4-)furyl]methyl group, [2,5-diethyl-(3- or 4-)furyl]methyl group, and [2,4,5-triethyl-3-furyl]methyl group.

Examples of the tetrahydrofuryl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) tetrahydrofuryl groups. Specific examples thereof include a (2- or 3-)(2,3,4,5-tetrahydrofuryl)methyl group, 2-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]ethyl group, 1-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]ethyl group, 3-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]propyl group, 2,3-di[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]propyl group, 4-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]butyl group, 3,4-di[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]butyl group, 1,1-dimethyl-2-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]ethyl group, 5-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]pentyl group, 6-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]hexyl group, 3,3-dimethyl-3-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]propyl group, 2-methyl-3-[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]propyl group, and 2,3,4-tri[(2- or 3-)(2,3,4,5-tetrahydrofuryl)]butyl group.

Examples of a 1,3-dioxolanyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) 1,3-dioxolanyl groups. Specific examples thereof include a [(2- or 4-)1,3-dioxolanyl]methyl group, 2-[(2- or 4-)1,3-dioxolanyl]ethyl group, 1-[(2- or 4-)1,3-dioxolanyl]ethyl group, 3-[(2- or 4-)1,3-dioxolanyl]propyl group, 4-[(2- or 4-)1,3-dioxolanyl]butyl group, 1,1-dimethyl-2-[(2- or 4-)1,3-dioxolanyl]ethyl group, 5-[(2- or 4-)1,3-dioxolanyl]pentyl group, 6-[(2- or 4-)1,3-dioxolanyl]hexyl group, 1-[(2- or 4-)1,3-dioxolanyl]isopropyl group, and 2-methyl-3-[(1-, 2-, or 4-)imidazolyl]propyl group.

Examples of the tetrahydropyranyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) tetrahydropyranyl groups. Specific examples thereof include a [(2-, 3-, or 4-)tetrahydropyranyl]methyl group, 2-[(2-, 3-, or 4-)tetrahydropyranyl]ethyl group, 1-[(2-, 3-, or 4-)tetrahydropyranyl]ethyl group, 3-[(2-, 3-, or 4-)tetrahydropyranyl]propyl group, 4-[(2-, 3-, or 4-)tetrahydropyranyl]butyl group, 1,1-dimethyl-2-[(2-, 3-, or 4-)tetrahydropyranyl]ethyl group, 5-[(2-, 3-, or 4-)tetrahydropyranyl]pentyl group, 6-[(2-, 3-, or 4-)tetrahydropyranyl]hexyl group, 1-[(2-, 3-, or 4-)tetrahydropyranyl]isopropyl group, and 2-methyl-3-[(2-, 3-, or 4-)tetrahydropyranyl]propyl group.

Examples of the pyrrolyl lower alkyl group (that may have a substituent of a lower alkyl group on the pyrrolyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) pyrrolyl groups on which 1 to 3 (preferably 1 to 2) lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present as a substituent(s). Specific examples thereof include a [(1-, 2-, or 3-)pyrrolyl]methyl group, 2-[(1-, 2-, or 3-)pyrrolyl]ethyl group, 1-[(1-, 2-, or 3-)pyrrolyl]ethyl group, 3-[(1-, 2-, or 3-)pyrrolyl]propyl group, 4-[(1-, 2-, or 3-)pyrrolyl]butyl group, 1,1-dimethyl-2-[(1-, 2-, or 3-)pyrrolyl]ethyl group, 5-[(1-, 2-, or 3-)pyrrolyl]pentyl group, 6-[(1-, 2-, or 3-)pyrrolyl]hexyl group, 1-[(1-, 2-, or 3-)pyrrolyl]isopropyl group, 2-methyl-3-[(1-, 2-, or 3-)pyrrolyl]propyl group, [1-methyl-(2- or 3-)pyrrolyl]methyl group, [1-ethyl-(2- or 3-)pyrrolyl]methyl group, [1-n-propyl-(2- or 3-)pyrrolyl]methyl group, [1-n-butyl-(2- or 3-)pyrrolyl]methyl group, [1-n-pentyl-(2- or 3-)pyrrolyl]methyl group, [1-n-hexyl-(2- or 3-)pyrrolyl]methyl group, 2-[5-methyl-(1-, 2-, 3-, or 4-)pyrrolyl]ethyl group, 1-[1-ethyl-(2- or 3-)pyrrolyl]ethyl group, 3-[1-ethyl-(2- or 3-)pyrrolyl]propyl group, 4-[1-n-propyl-(2- or 3-)pyrrolyl]butyl group, 5-[1-n-butyl-(2- or 3-)pyrrolyl]pentyl group, 6-[1-n-pentyl-(2- or 3-)pyrrolyl]hexyl group, [1,5-dimethyl-(2-, 3-, or 4-)pyrrolyl]methyl group, [1,3,5-trimethyl-2-pyrrolyl]methyl group, and [1,2,4-trimethyl-3-pyrrolyl]methyl group.

Examples of the lower alkyl group substituted with a dihydropyrazolyl group that may have an oxo group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having a 2,3-dihydropyrazolyl group or 4,5-dihydropyrazolyl group as a dihydropyrazolyl group, on which an oxo group may be present. Specific examples thereof include a 3-(2,3- or 4,5-)dihydropyrazolylmethyl group, 2-[4-(2,3- or 4,5-)dihydropyrazolyl]ethyl group, 1-[5-(2,3- or 4,5-)dihydropyrazolyl]ethyl group, 3-[3-(2,3- or 4,5-)dihydropyrazolyl]propyl group, 4-[4-(2,3- or 4,5-)dihydropyrazolyl]butyl group, 5-[1-(2,3- or 4,5-)dihydropyrazolyl]pentyl group, 6-[5-(2,3- or 4,5-)dihydropyrazolyl]hexyl group, 2-methyl-3-[1-(2,3- or 4,5-)dihydropyrazolyl]propyl group, 1,1-dimethyl-2-[3-(2,3- or 4,5-)dihydropyrazolyl]ethyl group, 5-oxo-4-(4,5-dihydropyrazolyl)methyl group, 2-[5-oxo-4-(4,5-dihydropyrazolyl)]ethyl group, and 3-[5-oxo-4-(4,5-dihydropyrazolyl)]propyl group.

Examples of the pyrazolyl lower alkyl group (that may have a substituent of a lower alkyl group on the pyrazolyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) pyrazolyl groups, on which 1 to 3 (preferably 1 to 2) lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present as a substituent(s). Specific examples thereof include a 3-pyrazolylmethyl group, 2-(4-pyrazolyl)ethyl group, 2-(1-pyrazolyl)ethyl group, 1-(5-pyrazolyl)ethyl group, 3-(3-pyrazolyl)propyl group, 4-(4-pyrazolyl)butyl group, 5-(1-pyrazolyl)pentyl group, 6-(5-pyrazolyl)hexyl group, 2-methyl-3-(1-pyrazolyl)propyl group, 1,1-dimethyl-2-(3-pyrazolyl)ethyl group, 1-methyl-3-pyrazolylmethyl group, 1-ethyl-3-pyrazolylmethyl group, 1-n-propyl-3-pyrazolylmethyl group, 1-n-butyl-3-pyrazolylmethyl group, 1-n-pentyl-3-pyrazolylmethyl group, 1-methyl-4-pyrazolylmethyl group, 5-methyl-3-pyrazolylmethyl group, 1-ethyl-4-pyrazolylmethyl group, 1-n-propyl-4-pyrazolylmethyl group, 1-n-butyl-4-pyrazolylmethyl group, 1-n-hexyl-4-pyrazolylmethyl group, 3-methyl-1-pyrazolylmethyl group, 3-ethyl-1-pyrazolylmethyl group, 3-n-propyl-1-pyrazolylmethyl group, 3-n-butyl-1-pyrazolylmethyl group, 1,5-dimethyl-3-pyrazolylmethyl group, 3,5-dimethyl-4-pyrazolylmethyl group, 3,4-dimethyl-1-pyrazolylmethyl group, 1,3-dimethyl-5-pyrazolylmethyl group, 3,4-diethyl-1-pyrazolylmethyl group, 3,4-di-n-propyl-1-pyrazolylmethyl group, 3,4-di-n-butyl-1-pyrazolylmethyl group, 1,3,5-trimethyl-4-pyrazolylmethyl group, 3,4,5-trimethyl-1-pyrazolylmethyl group, 3,4,5-triethyl-1-pyrazolylmethyl group, 3,4,5-tri-n-propyl-1-pyrazolylmethyl group, 3,4,5-tri-n-butyl-1-pyrazolylmethyl group, 1-methyl-5-pyrazolylmethyl group, 1-ethyl-5-pyrazolylmethyl group, 1-n-propyl-5-pyrazolylmethyl group, 1-n-butyl-5-pyrazolylmethyl group, 2-(3-pyrazolyl)ethyl group, 3-(3-pyrazolyl)propyl group, 4-(3-pyrazolyl)butyl group, 5-(3-pyrazolyl)pentyl group, 6-(3-pyrazolyl)hexyl group, 2-(1-(4-chlorophenyl)-3-pyrazolyl)ethyl group, 3-(1-methyl-3-pyrazolyl)propyl group, 3-(3-methyl-4-pyrazolyl)propyl group, 3-(5-methyl-4-pyrazolyl)propyl group, 3-(1,5-dimethyl-3-pyrazolyl)propyl group, 3-(1-ethyl-3-pyrazolyl)propyl group, 3-(1-n-propyl-3-pyrazolyl)propyl group, 3-(1-n-butyl-3-pyrazolyl)propyl group, 4-(1-methyl-3-pyrazolyl)butyl group, 4-(1-ethyl-3-pyrazolyl)butyl group, 4-(1-n-propyl-3-pyrazolyl)butyl group, 4-(1-n-butyl-3-pyrazolyl)butyl group, 5-(1-methyl-3-pyrazolyl)pentyl group, 5-(1-ethyl-3-pyrazolyl)pentyl group, 5-(1-n-propyl-3-pyrazolyl) group, 5-(1-n-butyl-3-pyrazolyl)pentyl group, 6-(1-methyl-3-pyrazolyl)hexyl group, 6-(1-ethyl-3-pyrazolyl)hexyl group, 6-(1-n-propyl-3-pyrazolyl)hexyl group, and 6-[1-(3-butyl)-3-pyrazolyl]hexyl group.

Examples of the imidazolyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) imidazolyl groups. Specific examples thereof include a [(1-, 2-, 4- or 5-)imidazolyl]methyl group, 2-[(1-, 2-, 4- or 5-)imidazolyl]ethyl group, 1-[(1-, 2-, 4- or 5-)imidazolyl]ethyl group, 3-[(1-, 2-, 4- or 5-)imidazolyl]propyl group, 4-[(1-, 2-, 4- or 5-)imidazolyl]butyl group, 1,1-dimethyl-2-[(1-, 2-, 4- or 5-)imidazolyl]ethyl group, 5-[(1-, 2-, 4- or 5-)imidazolyl]pentyl group, 6-[(1-, 2-, 4- or 5-)imidazolyl]hexyl group, 1-[(1-, 2-, 4- or 5-)imidazolyl]isopropyl group, and 2-methyl-3-[(1-, 2-, 4- or 5-)imidazolyl]propyl group.

Examples of the pyridyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) pyridyl groups. Specific examples thereof include a (2-, 3- or 4-)pyridylmethyl group, 2-[(2-, 3- or 4-)pyridyl]methyl group, 1-[(2-, 3- or 4-)pyridyl]ethyl group, 3-[(2-, 3- or 4-)pyridyl]propyl group, 4-[(2-, 3- or 4-)pyridyl]butyl group, 1,1-dimethyl-2-[(2-, 3- or 4-)pyridyl]ethyl group, 5-[(2-, 3- or 4-)pyridyl]pentyl group, 6-[(2-, 3- or 4-)pyridyl]hexyl group, 1-[(2-, 3- or 4-)pyridyl]isopropyl group, 2-methyl-3-[(2-, 3- or 4-)pyridyl]propyl group.

Examples of the pyrazinyl lower alkyl group (a lower alkyl group may be present as a substituent on the pyrazinyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) pyrazinyl groups on which 1 to 3 (preferably 1) lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present as a substituent(s). Specific examples thereof include a 2-pyrazinylmethyl group, 2-(2-pyrazinyl)ethyl group, 1-(2-pyrazinyl)ethyl group, 3-(2-pyrazinyl)propyl group, 4-(2-pyrazinyl)butyl group, 5-(2-pyrazinyl)pentyl group, 6-(2-pyrazinyl)hexyl group, 3-methyl-3-(2-pyrazinyl)propyl group, 1,1-dimethyl-2-(2-pyrazinyl)ethyl group, 3-methyl-2-pyrazinylmethyl group, 3-ethyl-2-pyrazinylmethyl group, 3-n-propyl-2-pyrazinylmethyl group, 3-n-butyl-2-pyrazinylmethyl group, 3-n-pentyl-2-pyrazinylmethyl group, 5-methyl-2-pyrazinylmethyl group, 5-ethyl-2-pyrazinylmethyl group, 5-n-propyl-2-pyrazinylmethyl group, 5-n-butyl-2-pyrazinylmethyl group, 6-methyl-2-pyrazinylmethyl group, 6-ethyl-2-pyrazinylmethyl group, 6-n-propyl-2-pyrazinylmethyl group, 6-n-butyl-2-pyrazinylmethyl group, 3,5-dimethyl-2-pyrazinylmethyl group, 3,5-diethyl-2-pyrazinylmethyl group, 3,5-di-n-propyl-2-pyrazinylmethyl group, 3,5-di-n-butyl-2-pyrazinylmethyl group, 2-(5-methyl-2-pyrazinyl)ethyl group, 2-(5-ethyl-2-pyrazinyl)ethyl group, 2-(5-n-propyl-2-pyrazinyl)ethyl group, 2-(5-n-butyl-2-pyrazinyl)ethyl group, 3-(5-methyl-2-pyrazinyl)propyl group, 3-(5-ethyl-2-pyrazinyl)propyl group, 3-(5-n-propyl-2-pyrazinyl)propyl group, 3-(5-n-butyl-2-pyrazinyl)propyl group, 4-(5-methyl-2-pyrazinyl)butyl group, 4-(5-ethyl-2-pyrazinyl)butyl group, 4-(5-n-propyl-2-pyrazinyl)butyl group, 4-(5-n-butyl-2-pyrazinyl)butyl group, 5-(5-methyl-2-pyrazinyl)pentyl group, 5-(5-ethyl-2-pyrazinyl)pentyl group, 5-(5-n-propyl-2-pyrazinyl)pentyl group, 5-(5-n-butyl-2-pyrazinyl)pentyl group, 6-(5-methyl-2-pyrazinyl)hexyl group, 6-(5-ethyl-2-pyrazinyl)hexyl group, 6-(5-n-propyl-2-pyrazinyl)hexyl group, and 6-(5-n-butyl-2-pyrazinyl)hexyl group.

Examples of the pyrrolidinyl lower alkyl group (a group selected from the group consisting of an oxo group and a lower alkyl group may be present as a substituent on the pyrrolidinyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) pyrrolidinyl groups, on which 1 to 3 (preferably 1) groups selected from the group consisting of an oxo group and a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present as a substituent(s). Specific examples thereof include a [(1-, 2-, or 3-)pyrrolidinyl]methyl group, 2-[(1-, 2-, or 3-)pyrrolidinyl]ethyl group, 1-[(1-, 2-, or 3-)pyrrolidinyl]ethyl group, 3-[(1-, 2-, or 3-)pyrrolidinyl]propyl group, 4-[(1-, 2-, or 3-)pyrrolidinyl]butyl group, 5-[(1-, 2-, or 3-)pyrrolidinyl]pentyl group, 6-[(1-, 2-, or 3-)pyrrolidinyl]hexyl group, 1-methyl-2-[(1-, 2-, or 3-)pyrrolidinyl]ethyl group, 1,1-dimethyl-2-[(1-, 2-, or 3-)pyrrolidinyl]ethyl group, 2-methyl-3-[(1-, 2-, or 3-)pyrrolidinyl)propyl group, 1-methyl-(2- or 3-)pyrrolidinylmethyl group, 1-ethyl-(2- or 3-)pyrrolidinylmethyl group, 1-n-propyl-(2- or 3-)pyrrolidinylmethyl group, 1-n-butyl-(2- or 3-)pyrrolidinylmethyl group, 1-n-pentyl-(2- or 3-)pyrrolidinylmethyl group, 1-n-hexyl-(2- or 3-)pyrrolidinylmethyl group, 2-methyl-1-pyrrolidinylmethyl group, 2-ethyl-1-pyrrolidinylmethyl group, 2-n-propyl-1-pyrrolidinylmethyl group, 2-n-butyl-1-pyrrolidinylmethyl group, 2-n-pentyl-1-pyrrolidinylmethyl group, 2-n-hexyl-1-pyrrolidinylmethyl group, 3-methyl-2-pyrrolidinylmethyl group, 3-ethyl-2-pyrrolidinylmethyl group, 3-n-propyl-2-pyrrolidinylmethyl group, 3-n-butyl-2-pyrrolidinylmethyl group, 1,5-dimethyl-(2- or 3-)pyrrolidinylmethyl group, 1,5-di-ethyl-(2- or 3-)pyrrolidinylmethyl group, 1,5-di-n-propyl-(2- or 3-)pyrrolidinylmethyl group, 1,5-di-n-butyl-(2- or 3-)pyrrolidinylmethyl group, 1,4,5-triethyl-(2- or 3-)pyrrolidinylmethyl group, 1,4,5-tri-n-propyl-(2- or 3-)pyrrolidinylmethyl group, 1,4,5-tri-n-butyl-(2- or 3-)pyrrolidinylmethyl group, 3-[2-oxo-(1-pyrrolidinyl)propyl]group, 3-[5-oxo-(2-, 3-, or 4-)pyrrolidinyl]propyl group, and 3-[1-methyl-5-oxo-(2-, 3-, or 4-)pyrrolidinyl]propyl group.

Examples of the piperidyl lower alkyl group (that may have as a substituent on the piperidyl group, a group selected from the group consisting of a benzoyl group and a lower alkanoyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) piperidyl groups having 1 to 3 (preferably 1) groups, as a substituent(s), selected from the group consisting of a benzoyl group and a lower alkanoyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) on the piperidyl group(s). Specific examples thereof include a (1-, 2-, 3-, or 4-)piperidylmethyl group, 2-[(1-, 2-, 3-, or 4-)piperidyl]ethyl group, 2-[1-benzoyl-(2-, 3-, or 4-)piperidyl]ethyl group, 2-[1-acetyl-(2-, 3-, or 4-)piperidyl]ethyl group, 2-[1-butyryl-(2-, 3-, or 4-)piperidyl]ethyl group, 1-[(1-, 2-, 3-, or 4-)piperidyl]ethyl group, 3-[(1-, 2-, 3-, or 4-)piperidyl]propyl group, 4-[(1-, 2-, 3-, or 4-)piperidyl]butyl group, 1,1-dimethyl-2-[(1-, 2-, 3-, or 4-)piperidyl]ethyl group, 5-[(1-, 2-, 3-, or 4-)piperidyl]pentyl group, 6-[(1-, 2-, 3-, or 4-)piperidyl]hexyl group, 1-[(1-, 2-, 3-, or 4-)piperidyl]isopropyl group, and 2-methyl-3-[(1-, 2-, 3-, or 4-)piperidyl]propyl group.

Examples of the piperazinyl lower alkyl group (that may have a lower alkyl group as a substituent on the piperazinyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) piperazinyl groups, on which 1 to 3 (preferably 1) lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present as a substituent(s). Specific examples thereof include a 1-piperazinylmethyl group, 2-piperazinylmethyl group, 2-(1-piperazinyl)ethyl group, 2-(2-piperazinyl)ethyl group, 1-(1-piperazinyl)ethyl group, 1-(2-piperazinyl)ethyl group, 3-(1-piperazinyl)propyl group, 3-(2-piperazinyl)propyl group, 4-(1-piperazinyl)butyl group, 4-(2-piperazinyl)butyl group, 2-(4-ethyl-2-piperazinyl)ethyl group, 1-(4-n-propyl-2-piperazinyl)ethyl group, 2-(4-n-butyl-2-piperazinyl)ethyl group, 2-(4-n-pentyl-2-piperazinyl)ethyl group, 1-(4-n-hexyl-2-piperazinyl)ethyl group, 2-)5-methyl-2-piperazinyl)ethyl group, 1-(5-ethyl-2-piperazinyl)ethyl group, 2-(5-n-propyl-2-piperazinyl)ethyl group, 1-(5-n-butyl-2-piperazinyl)ethyl group, 2-(5-n-pentyl-2-piperazinyl)ethyl group, 1-(5-n-hexyl-2-piperazinyl)ethyl group, 2-(6-methyl-2-piperazinyl)ethyl group, 1-(6-ethyl-2-piperazinyl)ethyl group, 2-(6-n-propyl-2-piperazinyl)ethyl group, 1-(6-n-butyl-2-piperazinyl)ethyl group, 2-(6-n-pentyl-2-piperazinyl)ethyl group, 2-(6-n-hexyl-2-piperazinyl)ethyl group, 3-(2-methyl-1-piperazinyl)ethyl group, 3-(2-ethyl-1-piperazinyl)ethyl group, 3-(2-n-propyl-1-piperazinyl)ethyl group, 3-(2-n-butyl-1-piperazinyl)ethyl group, 3-(2-n-pentyl-1-piperazinyl)ethyl group, 3-(2-n-hexyl-1-piperazinyl)ethyl group, 3-(3-methyl-1-piperazinyl)ethyl group, 3-(3-ethyl-1-piperazinyl)ethyl group, 3-(3-n-propyl-1-piperazinyl)ethyl group, 3-(3-n-butyl-1-piperazinyl)ethyl group, 3-(3-n-pentyl-1-piperazinyl)ethyl group, 3-(3-n-hexyl-1-piperazinyl)ethyl group, 3-(4-methyl-1-piperazinyl)ethyl group, 3-(4-ethyl-1-piperazinyl)ethyl group, 3-(4-n-propyl-1-piperazinyl)ethyl group, 3-(4-n-butyl-1-piperazinyl)ethyl group, 3-(4-n-pentyl-1-piperazinyl)ethyl group, 6-(5-n-butyl-2-piperazinyl)hexyl group, 6-(5-n-pentyl-2-piperazinyl)hexyl group, 6-(5-n-hexyl-2-piperazinyl)hexyl group, 6-(6-methyl-2-piperazinyl)hexyl group, 6-(6-ethyl-2-piperazinyl)hexyl group, 6-(6-n-propyl-2-piperazinyl)hexyl group, 6-(6-n-butyl-2-piperazinyl)hexyl group, 6-(6-n-pentyl-2-piperazinyl)hexyl group, 6-(6-n-hexyl-2-piperazinyl)hexyl group, 2,3-dimethyl-1-piperazinylmethyl group, 3,3-dimethyl-1-piperazinylmethyl group, and 2-(1,3,4-trimethyl-2-piperazinyl)ethyl group.

Examples of the morpholinyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) morpholinyl groups. Specific examples thereof include a 2-morpholinylmethyl group, 3-morpholinylmethyl group, 4-morpholinylmethyl group, 2-(2-morpholinyl)ethyl group, 2-(3-morpholinyl)ethyl group, 2-(4-morpholinyl)ethyl group, 1-(2-morpholinyl)ethyl group, 1-(3-morpholinyl)ethyl group, 1-(4-morpholinyl)ethyl group, 3-(2-morpholinyl)propyl group, 3-(3-morpholinyl)propyl group, 3-(4-morpholinyl)propyl group, 4-(2-morpholinyl)butyl group, 4-(3-morpholinyl)butyl group, 4-(4-morpholinyl)butyl group, 5-(2-morpholinyl)pentyl group, 5-(3-morpholinyl)pentyl group, 5-(4-morpholinyl)pentyl group, 6-(2-morpholinyl)hexyl group, 6-(3-morpholinyl)hexyl group, 6-(4-morpholinyl)hexyl group, 3-methyl-3-(2-morpholinyl)propyl group, 3-methyl-3-(3-morpholinyl)propyl group, 3-methyl-3-(4-morpholinyl)propyl group, 1,1-dimethyl-2-(2-morpholinyl)ethyl group, 1,1-dimethyl-2-(3-morpholinyl)ethyl group, and 1,1-dimethyl-2-(4-morpholinyl)ethyl group.

Example of a thienyl lower alkyl group (that may have a lower alkyl group as a substituent on the thienyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) thienyl groups, on which 1 to 3 (preferably 1) lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present as a substituent(s). Specific examples thereof include a (2- or 3-)thienylmethyl group, 2-[(2- or 3-)thienyl]ethyl group, 1-[(2- or 3-)thienyl]ethyl group, 3-[(2- or 3-)thienyl]propyl group, 4-[(2- or 3-)thienyl]butyl group, 5-[(2- or 3-)thienyl]pentyl group, 6-[(2- or 3-)thienyl]hexyl group, 1,1-dimethyl-2-[(2- or 3-)thienyl]ethyl group, 2-methyl-3-[(2- or 3-)thienyl]propyl group, 3-methyl-(2-, 4-, or 5-)-thienylmethyl group, [5-methyl-(2,3- or 4-)thienyl]methyl group, [4-ethyl-(2- or 3-)thienyl]methyl group, [5-n-propyl-(2,3- or 4-)thienyl]methyl group, [3-n-butyl-(2-, 4-, or 5-)-thienyl]]]methyl group, [4,5-dimethyl-(2- or 3-)thienyl]methyl group, (3,4,5-trimethyl-2-thienyl)methyl group, 2-[3-methyl-(2-, 4-, or 5-)-thienyl]ethyl group, 1-[4-n-pentyl-(2- or 3-)thienyl]ethyl group, 3-[3-hexyl-2-thienyl]propyl group, 4-[4,5-dimethyl-(2- or 3-)thienyl]butyl group, 5-(2,4,5-trimethyl-3-thienyl)pentyl group, and 6-[5-ethyl-(2-, 3-, or 4-)thienyl]hexyl group.

Examples of the thiazolyl group include a (2-, 4- or 5-) thiazolyl group.

Examples of the thiazolyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) thiazolyl groups. Specific examples thereof include a (2-, 4-, or 5-)thiazolylmethyl group, 2-[(2-, 4-, or 5-)thiazolyl)ethyl group, 1-[(2-, 4-, or 5-)thiazolyl]ethyl group, 3-[(2-, 4-, or 5-)thiazolyl]propyl group, 4-[(2-, 4-, or 5-)thiazolyl]butyl group, 5-[(2-, 4-, or 5-)thiazolyl)]pentyl group, 6-[(2-, 4-, or 5-)thiazolyl)]hexyl group, 1,1-dimethyl-2-[(2-, 4-, or 5-)thiazolyl]ethyl group, and [2-methyl-3-[(2-, 4-, or 5-)thiazolyl]propyl group.

Examples of the dihydrobenzofuryl group include a 2,3-dihydro-(2-, 3-, 4-, 5-, 6- or 7-)benzofuryl group.

Examples of the dihydrobenzofuryl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) dihydrobenzofuryl groups. Specific examples thereof include a 2,3-dihydro-4-benzofurylmethyl group, 2-(2,3-dihydro-4-benzofuryl)ethyl group, 3-(2,3-dihydro-4-benzofuryl)propyl group, 4-(2,3-dihydro-4-benzofuryl)butyl group, 5-(2,3-dihydro-4-benzofuryl)pentyl group, 6-(2,3-dihydro-4-benzofuryl)hexyl group, 2,3-dihydro-5-benzofurylmethyl group, 2-(2,3-dihydro-5-benzofuryl)ethyl group, 3-(2,3-dihydro-5-benzofuryl)propyl group, 4-(2,3-dihydro-5-benzofuryl)butyl group, 2,3-dihydro-6-benzofurylmethyl group, 2-(2,3-dihydro-6-benzofuryl)ethyl group, 3-(2,3-dihydro-6-benzofuryl)propyl group, 4-(2,3-dihydro-6-benzofuryl)butyl group, 5-(2,3-dihydro-6-benzofuryl)pentyl group, 2,3-dihydro-7-benzofurylmethyl group, 2,3-dihydro-7-benzofurylethyl group, 3-(2,3-dihydro-7-benzofuryl)propyl group, 4-(2,3-dihydro-7-benzofuryl)butyl group, and 6-(2,3-dihydro-7-benzofuryl)hexyl group.

Examples of the benzopyranyl lower alkyl group (that may have an oxo group as a substituent on the benzopyranyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) benzopyranyl groups on which an oxo group may be present as a substituent. Specific examples thereof include a (4H-1-benzopyran-2-yl)methyl group, 2-(4H-1-benzopyran-2-yl)ethyl group, 3-(4H-1-benzopyran-2-yl)propyl group, 4-(4H-1-benzopyran-2-yl)butyl group, 5-(4H-1-benzopyran-2-yl)pentyl group, 6-(4H-1-benzopyran-2-yl)hexyl group, (4H-1-benzopyran-3-yl)methyl group, 2-(4H-1-benzopyran-3-yl)ethyl group, 3-(4H-1-benzopyran-3-yl)propyl group, 4-(4H-1-benzopyran-3-yl)butyl group, 5-(4H-1-benzopyran-3-yl)pentyl group, 6-(4H-1-benzopyran-3-yl)hexyl group, (4H-1-benzopyran-4-yl)methyl group, 2-(4H-1-benzopyran-4-yl)ethyl group, 3-(4H-1-benzopyran-4-yl)propyl group, 4-(4H-1-benzopyran-4-yl)butyl group, 5-(4H-1-benzopyran-4-yl)pentyl group, 6-(4H-1-benzopyran-4-yl)hexyl group, (2H-1-benzopyran-2-yl)methyl group, 2-(2H-1-benzopyran-2-yl)ethyl group, 3-(2H-1-benzopyran-2-yl)propyl group, 4-(2H-1-benzopyran-2-yl)butyl group, 5-(2H-1-benzopyran-2-yl)pentyl group, 6-(2H-1-benzopyran-2-yl)hexyl group, (2H-1-benzopyran-3-yl)methyl group, 2-(2H-1-benzopyran-3-yl)ethyl group, 3-(2H-1-benzopyran-3-yl)propyl group, 4-(2H-1-benzopyran-3-yl)butyl group, 5-(2H-1-benzopyran-3-yl)pentyl group, 6-(2H-1-benzopyran-3-yl)hexyl group, (2H-1-benzopyran-4-yl)methyl group, 2-(2H-1-benzopyran-4-yl)ethyl group, 3-(2H-1-benzopyran-4-yl)propyl group, 4-(2H-1-benzopyran-4-yl)butyl group, 5-(2H-1-benzopyran-4-yl)pentyl group, 6-(2H-1-benzopyran-4-yl)hexyl group, (1H-2-benzopyran-1-yl)methyl group, 2-(1H-2-benzopyran-1-yl)ethyl group, 3-(1H-2-benzopyran-1-yl)propyl group, 4-(1H-2-benzopyran-1-yl)butyl group, 5-(1H-2-benzopyran-1-yl)pentyl group, 6-(1H-2-benzopyran-1-yl)hexyl group, (1H-2-benzopyran-3-yl)methyl group, 2-(1H-2-benzopyran-3-yl)ethyl group, 3-(1H-2-benzopyran-3-yl)propyl group, 4-(1H-2-benzopyran-3-yl)butyl group, 5-(1H-2-benzopyran-3-yl)pentyl group, 6-(1H-2-benzopyran-3-yl)hexyl group, (1H-2-benzopyran-3-yl)methyl group, 2-(1H-2-benzopyran-4-yl)ethyl group, 3-(1H-2-benzopyran-4-yl)propyl group, 4-(1H-2-benzopyran-4-yl)butyl group, 5-(1H-2-benzopyran-4-yl)pentyl group, 6-(1H-2-benzopyran-4-yl)hexyl group, (4-oxo-4H-1-benzopyran-2-yl)methyl group, 2-(4-oxo-4H-1-benzopyran-2-yl)ethyl group, 3-(4-oxo-4H-1-benzopyran-2-yl)propyl group, 4-(4-oxo-4H-1-benzopyran-2-yl)butyl group, 5-(4-oxo-4H-1-benzopyran-2-yl)pentyl group, 6-(4-oxo-4H-1-benzopyran-2-yl)hexyl group, (4-oxo-4H-1-benzopyran-3-yl)methyl group, 2-(4-oxo-4H-1-benzopyran-3-yl)ethyl group, 3-(4-oxo-4H-1-benzopyran-3-yl)propyl group, 4-(4-oxo-4H-1-benzopyran-3-yl)butyl group, 5-(4-oxo-4H-1-benzopyran-3-yl)pentyl group, 6-(4-oxo-4H-1-benzopyran-3-yl)hexyl group, (4-oxo-4H-1-benzopyran-4-yl)methyl group, (2-oxo-2H-1-benzopyran-3-yl)methyl group, 2-(2-oxo-2H-1-benzopyran-3-yl)ethyl group, 3-(2-oxo-2H-1-benzopyran-3-yl)propyl group, 4-(2-oxo-2H-1-benzopyran-3-yl)butyl group, 5-(2-oxo-2H-1-benzopyran-3-yl)pentyl group, 6-(2-oxo-2H-1-benzopyran-3-yl)hexyl group, (2-oxo-2H-1-benzopyran-4-yl)methyl group, 2-(2-oxo-2H-1-benzopyran-4-yl)ethyl group, 3-(2-oxo-2H-1-benzopyran-4-yl)propyl group, 4-(2-oxo-2H-1-benzopyran-4-yl)butyl group, 5-(2-oxo-2H-1-benzopyran-4-yl)pentyl group, 6-(2-oxo-2H-1-benzopyran-4-yl)hexyl group, (1-oxo-1H-2-benzopyran-3-yl)methyl group, 2-(1-oxo-1H-2-benzopyran-3-yl)ethyl group, 3-(1-oxo-1H-2-benzopyran-3-yl)propyl group, 4-(1-oxo-1H-2-benzopyran-3-yl)butyl group, 5-(1-oxo-1H-2-benzopyran-3-yl)pentyl group, 6-(1-oxo-1H-2-benzopyran-3-yl)hexyl group, (1-oxo-1H-2-benzopyran-4-yl)methyl group, 2-(1-oxo-1H-2-benzopyran-4-yl)ethyl group, 3-(1-oxo-1H-2-benzopyran-4-yl)propyl group, 4-(1-oxo-1H-2-benzopyran-4-yl)butyl group, 5-(1-oxo-1H-2-benzopyran-4-yl)pentyl group, and 6-(1-oxo-1H-2-benzopyran-4-yl)hexyl group.

Examples of the benzimidazolyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) benzimidazolyl groups. Specific examples thereof include a 1-benzimidazolylmethyl group, 2-(1-benzimidazolyl)ethyl group, 3-(1-benzimidazolyl)propyl group, 4-(1-benzimidazolyl)butyl group, 5-(1-benzimidazolyl)pentyl group, 6-(1-benzimidazolyl)hexyl group, 2-benzimidazolylmethyl group, 2-(2-benzimidazolyl)ethyl group, 3-(2-benzimidazolyl)propyl group, 4-(2-benzimidazolyl)butyl group, 5-(2-benzimidazolyl)pentyl group, and 6-(2-benzimidazolyl)hexyl group.

Examples of the indolyl lower alkyl group that may have a lower alkoxycarbonyl group on the lower alkyl group include a lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) as illustrated above that may have 1 to 3 (preferably 1) lower alkoxycarbonyl groups as illustrated above (preferably linear or branched alkoxycarbonyl groups having 1 to 6 carbon atoms) that may have 1 to 2 (preferably 1) indolyl groups. Specific examples thereof include an indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylmethyl group, 2-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylethyl group, 3-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylpropyl group, 4-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylbutyl group, 5-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylpentyl group, 6-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylhexyl group, 3-methyl-3-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylpropyl group, 1,1-dimethyl-2-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylethyl group, and 1-methoxycarbonyl-2-indol(-1-, -2-, -3-, -4-, -5-, -6-, or -7-)ylethyl group.

Examples of the imidazolyl lower alkyl group having an substituent selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group on the lower alkyl group include an imidazolyl lower alkyl group having a 1 to 3, preferably 1, substituents selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group as illustrated above on the alkyl group whose lower alkyl moiety is the same as that illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a carbamoyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, methoxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, ethoxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, n-butoxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, isobutoxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, tert-butoxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, sec-butoxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, n-pentyloxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, neopentyloxy-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, n-hexyloxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, isohexyloxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, 3-methylpentyloxycarbonyl-[(1-, 2-, 4-, or 5-)imidazolyl]methyl group, 1-carbamoyl-2-[(1-, 2-, 4-, or 5-)imidazolyl]ethyl group, 1-methoxycarbonyl-2-[(1-, 2-, 4-, or 5-)imidazolyl]ethyl group, 1,1-dimethoxycarbonyl-2-[(1-, 2-, 4-, or 5-)imidazolyl]ethyl group, 1,1-dicarbamoyl-2-[(1-, 2-, 4-, or 5-)imidazolyl]ethyl group, 2-carbamoyl-1-[(1-, 2-, 4-, or 5-)imidazolyl]ethyl group, 2-methoxycarbonyl-3-[(1-, 2-, 4-, or 5-)imidazolyl]propyl group, 2-carbamoyl-4-[(1-, 2-, 4-, or 5-)imidazolyl]butyl group, 1-methyl-1-carbamoylmethyl-2-[(1-, 2-, 4-, or 5-)imidazolyl]ethyl group, 2-methoxycarbonyl-5-[(1-, 2-, 4-, or 5-)imidazolyl]pentyl group, 3-carbamoyl-6-[(1-, 2-, 4-, or 5-)imidazolyl]hexyl group, 2-methoxycarbonyl-1-[(1-, 2-, 4-, or 5-)imidazolyl]isopropyl group, and 2-carbamoylmethyl-3-[(1-, 2-, 4-, or 5-)imidazolyl]propyl group.

Examples of the pyridyl group that may have a group selected from the group consisting of a lower alkyl group, lower alkoxy group, and lower alkylthio lower alkyl group, as a substituent include a pyridyl group that may have 1 to 4 (preferably 1) groups, as a substituent(s), which are selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms), a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms), and a lower alkylthio lower alkyl group in which the two lower alkyl moieties each are composed of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 5-ethyl-3-pyridyl group, 2-n-propyl-3-pyridyl group, 4-n-butyl-2-pyridyl group, 4-tert-butyl-2-pyridyl group, 5-n-pentyl-3-pyridyl group, 4-n-hexyl-2-pyridyl group, 4-methoxy-2-pyridyl group, 5-methoxy-2-pyridyl group, 2-methylthiomethyl-3-pyridyl group, 5-ethylthiomethyl-2-pyridyl group, 4-n-propylthiomethyl-2-pyridyl group, 3-n-butylthiomethyl-2-pyridyl group, 5-n-pentylthiomethyl-3-pyridyl group, 4-n-hexylthiomethyl-3-pyridyl group, 2-(2-methylthioethyl)-3-pyridyl group, 2-(3-methylthiopropyl)-4-pyridyl group, 3-(4-methylthiobutyl)-4-pyridyl group, 3-(5-methylthiopentyl)-2-pyridyl group, 4-(6-methylthiohexyl)-2-pyridyl group, 3,4-dimethyl-2-pyridyl group, 2,4,6-triethyl-3-pyridyl group, 2,3,5,6-tetramethyl-4-pyridyl group, and 2-methyl-3-methylthiomethyl-4-pyridyl group.

Examples of the pyrrolidinyl group that may have a group selected from the group consisting of a lower alkyl group, lower alkoxycarbonyl group, lower alkanoyl group, and aroyl group as a substituent include a pyrrolidinyl group that may have 1 to 3, preferably 1 group, as a substituent(s), which is selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms), a lower alkoxycarbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms) a lower alkanoyl group as described above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms), and an aroyl group (preferably a benzoyl group). Specific examples thereof include a pyrrolidin-1-yl group, pyrrolidin-2-yl group, pyrrolidin-3-yl group, 1-methylpyrrolidin-3-yl group, 2-ethylpyrrolidin-3-yl group, 3-n-propylpyrrolidin-3-yl group, 4-n-butylpyrrolidin-3-yl group, 1-tert-butylpyrrolidin-3-yl group, 5-n-pentylpyrrolidin-3-yl group, 1-n-hexylpyrrolidin-2-yl group, 2-methoxycarbonyl-2-yl group, 3-ethoxycarbonylpyrrolidin-2-yl group, 1-tert-butoxycarbonylpyrrolidin-3-yl group, 4-propoxycarbonylpyrrolidin-2-yl group, 5-butoxycarbonylpyrrolidin-2-yl group, 1-pentoxycarbonyl-2-yl group, 2-hexyloxycarbonylpyrrolidin-2-yl group, 1,3-dimethoxycarbonylpyrrolidin-2-yl group, 3,4,5-triethylpyrrolidin-2-yl group, 2,3,4,5-tetramethylpyrrolidin-1-yl group, 2,4-dimethoxycarbonylpyrrolidin-1-yl group, 3,4,5-triethoxycarbonylpyrrolidin-1-yl group, 2-methyl-4-methoxycarbonylpyrrolidin-1-yl group, 1-benzoylpyrrolidin-3-yl group, 1-acetylpyrrolidin-3-yl group, and 1-butyrylpyrrolidin-3-yl group.

Examples of the piperidyl group that may have a group as a substituent selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and an aroyl group that may have a group selected from the group consisting of a lower alkyl group and a halogen atom include a piperidyl group that may have 1 to 5 (preferably 1 to 4) groups, as a substituent(s), which are selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms);

a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms); and

an aroyl group that may have 1 to 3 groups (preferably 1 group) selected from the group consisting of a lower alkyl group as illustrated above and a halogen atom as illustrated above (preferably a benzoyl group). Specific examples thereof include a 1-piperidyl group, 2-piperidyl group, 3-piperidyl group, 4-piperidyl group, 1-methyl-4-piperidyl group, 2-ethyl-4-piperidyl group, 3-n-propyl-4-piperidyl group, 4-n-butyl-4-piperidyl group, 1-n-pentyl-4-piperidyl group, 2-n-hexyl-4-piperidyl group, 1-methoxycarbonyl-4-piperidyl group, 1-ethoxycarbonyl-4-piperidyl group, 4-n-propoxycarbonyl-4-piperidyl group, 5-n-butoxycarbonyl-4-piperidyl group, 1-tert-butoxycarbonyl-4-piperidyl group, 1-formyl-4-piperidyl group, 1-acetyl-4-piperidyl group, 1-butyryl-4-piperidyl group, 1-butyryl-3-piperidyl group, 2-propionyl-4-piperidyl group, 3-butyryl-4-piperidyl group, 4-isobutyryl-4-piperidyl group, 1-n-pentanoyl-4-piperidyl group, 2-tert-butylcarbonyl-4-piperidyl group, 3-n-hexanoyl-4-piperidyl group, 1-benzoyl-4-piperidyl group, 1-benzoyl-3-piperidyl group, 1-(2-, 3-, or 4-chlorobenzoyl)-4-piperidyl group, 1-(2-, 3-, or 4-fluorobenzoyl)-4-piperidyl group, 1-(2-, 3-, or 4-methylbenzoyl)-4-piperidyl group, 2,6-dimethyl-4-piperidyl group, 2,4,6-trimethyl-3-piperidyl group, 2,2,6,6-tetramethyl-4-piperidyl group, and 2,2,4,4,6-pentamethyl-3-piperidyl group.

Examples of the tetrahydrofuryl group that may have an oxo group include a 2-tetrahydrofuryl group, 3-tetrahydrofuryl group, 3-oxo-2-tetrahydrofuryl group, 4-oxo-2-tetrahydrofuryl group, 5-oxo-2-tetrahydrofuryl group, 2-oxo-3-tetrahydrofuryl group, 4-oxo-3-tetrahydrofuryl group, and 5-oxo-4-tetrahydrofuryl group.

Examples of the hexahydroazepinyl group that may have an oxo group include 2-hexahydroazepinyl group, 3-hexahydroazepinyl group, 4-hexahydroazepinyl group, 2-oxo-3-hexahydroazepinyl group, 3-oxo-2-hexahydroazepinyl group, 4-oxo-2-hexahydroazepinyl group, 5-oxo-2-hexahydroazepinyl group, and 6-oxo-2-hexahydroazepinyl group.

Examples of the pyrazolyl group that may have a group selected from the group consisting of a lower alkyl group, aryl group, and furyl group as a substituent include a pyrazolyl group that may have 1 to 3 (preferably 1 to 2) groups, as a substituent(s), which are selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

an aryl group as illustrated above; and

a furyl group. Specific examples thereof include a 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 1-methyl-5-pyrazolyl group, 1-ethyl-5-pyrazolyl group, 3-n-propyl-5-pyrazolyl group, 4-n-butyl-5-pyrazolyl group, 1-tert-butyl-4-pyrazolyl group, 1-n-pentyl-4-pyrazolyl group, 3-n-hexyl-4-pyrazolyl group, 3-phenyl-5-pyrazolyl group, 1-(2-naphthyl)-3-pyrazolyl group, 4-(2-methylphenyl)-3-pyrazolyl group, 5-(3-ethylphenyl)-3-pyrazolyl group, 1-(4-n-propylphenyl)-4-pyrazolyl group, 3-(2-n-butylphenyl)-4-pyrazolyl group, 5-(3-n-pentylphenyl)-4-pyrazolyl group, 1-(4-n-hexylphenyl)-5-pyrazolyl group, 3-(2-isobutylphenyl)-5-pyrazolyl group, 4-(3-tert-butylphenyl)-5-pyrazolyl group, 3-(2-chlorophenyl)-1-pyrazolyl group, 4-(3-fluorophenyl)-1-pyrazolyl group, 5-(4-bromophenyl)-1-pyrazolyl group, 1-(2-aminophenyl)-3-pyrazolyl group, 4-(2,3-dimethylphenyl)-3-pyrazolyl group, 5-(3,4,5-trimethylphenyl)-3-pyrazolyl group, 1-(2,3-diaminophenyl)-4-pyrazolyl group, 3-(2-furyl)-5-pyrazolyl group, 1,3-dimethyl-5-pyrazolyl group, 1,3,4-triethyl-5-pyrazolyl group, 1,3,5-trimethyl-4-pyrazolyl group, and 1-methyl-3-phenyl-5-pyrazolyl group.

Examples of the thiadiazolyl group include a 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group or 1,3,4-thiadiazolyl group.

Examples of the thiadiazolyl group that may have a lower alkyl group include a thiadiazolyl group as illustrated above that may have 1 to 3, preferably 1, lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a 4- or 5-(1,2,3-thiadiazolyl) group, 3- or 5-(1,2,4-thiadiazolyl) group, 3-(1,2,5-thiadiazolyl) group, 2-(1,3,4-thiadiazolyl) group, 5-methyl-1,3,4-thiadiazol-2-yl group, 4-ethyl-1,2,3-thiadiazol-5-yl group, 5-n-propyl-1,2,4-thiadiazol-3-yl group, 5-n-butyl-1,3,4-thiadiazol-2-yl group, 4-tert-butyl-1,2,3-thiadiazol-5-yl group, 5-n-pentyl-1,2,4-thiadiazol-3-yl group, and 5-n-hexyl-1,3,4-thiadiazol-2-yl group.

Examples of an isoxazolyl group that may have a lower alkyl group include an isoxazolyl group that may have 1 to 2 lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 3-methyl-5-isoxazolyl group, 4-ethyl-5-isoxazolyl group, 4-n-propyl-3-isoxazolyl group, 5-methyl-3-isoxazolyl group, 5-n-butyl-3-isoxazolyl group, 3-tert-butyl-4-isoxazolyl group, 5-n-pentyl-4-isoxazolyl group, 3-n-hexyl-5-isoxazolyl group, and 3,4-dimethyl-5-isoxazolyl group.

Examples of the indazolyl group include a (1-, 3-, 4-, 5-, 6- or 7-)indazolyl group.

Examples of the tetrahydrobenzothiazolyl group include a (2-, 4-, 5-, 6-, or 7-)(4,5,6,7-tetrahydrobenzothiazolyl) group.

Examples of the tetrahydroquinolyl group include a (1-, 2-, 4-, 5-, 6- or -8)(1,2,3,4-tetrahydroquinolyl group.

Example of a tetrahydroquinolyl group that may have a group selected from the group consisting of a lower alkyl group, lower alkoxy group, halogen atom and oxo group as a substituent include a tetrahydroquinolyl group as illustrated above that may have 1 to 3 (preferably 1 to 2) groups, as a substituent(s), which are selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms); a halogen atom; and

an oxo group. Specific examples thereof include a 1-(1,2,3,4-tetrahydroquinolyl) group, 2-(1,2,3,4-tetrahydroquinolyl) group, 3-(1,2,3,4-tetrahydroquinolyl) group, 4-(1,2,3,4-tetrahydroquinolyl) group, 5-(1,2,3,4-tetrahydroquinolyl) group, 6-(1,2,3,4-tetrahydroquinolyl) group, 7-(1,2,3,4-tetrahydroquinolyl) group, 8-(1,2,3,4-tetrahydroquinolyl) group, 2-methyl-3-(1,2,3,4-tetrahydroquinolyl) group, 3-ethyl-2-(1,2,3,4-tetrahydroquinolyl) group, 4-n-propyl-2-(1,2,3,4-tetrahydroquinolyl) group, 5-n-butyl-3-(1,2,3,4-tetrahydroquinolyl) group, 6-tert-butyl-3-(1,2,3,4-tetrahydroquinolyl) group, 7-n-pentyl-2-(1,2,3,4-tetrahydroquinolyl) group, 8-n-hexyl-2-(1,2,3,4-tetrahydroquinolyl) group, 2-methoxy-4-(1,2,3,4-tetrahydroquinolyl) group, 3-ethoxy-4-(1,2,3,4-tetrahydroquinolyl) group, 4-propoxy-5-(1,2,3,4-tetrahydroquinolyl) group, 5-butoxy-6-(1,2,3,4-tetrahydroquinolyl) group, 6-pentoxy-7-(1,2,3,4-tetrahydroquinolyl) group, 7-hexyloxy-8-(1,2,3,4-tetrahydroquinolyl) group, 4-oxo-3-(1,2,3,4-tetrahydroquinolyl) group, 2-oxo-(1-, 3-, 4-, 5-, 6-, 7-, or 8-)-(1,2,3,4-tetrahydroquinolyl) group, 2-oxo-8-methyl-(3-, 4-, 5-, 6-, or 7-)-(1,2,3,4-tetrahydroquinolyl) group, 2-oxo-8-methoxy-3-(1,2,3,4-tetrahydroquinolyl) group, 2-oxo-5-methoxy-(1-, 3-, 4-, 6-, 7-, or 8-)-(1,2,3,4-tetrahydroquinolyl) group, 2-oxo-8-fluoro-(3-, 4-, 5-, 6-, or 7-)-(1,2,3,4-tetrahydroquinolyl)group, and 2-oxo-6,8-dimethyl-3-(1,2,3,4-tetrahydroquinolyl) group.

Examples of the quinolyl group include a 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, and 8-quinolyl group. Examples of the quinolyl group that may have a lower alkyl group include a quinolyl group that may have 1 to 2 lower alkyl groups as illustrated above (preferably linear or branched alkyl groups having 1 to 6 carbon atoms). Specific examples thereof include a 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group, 2-methyl-6-quinolyl group, 4-ethyl-5-quinolyl group, 4-n-propyl-3-quinolyl group, 5-methyl-3-quinolyl group, 5-n-butyl-3-quinolyl group, 3-tert-butyl-4-quinolyl group, 5-n-pentyll-4-quinolyl group, 3-n-hexyl-5-quinolyl group and 3,4-dimethyl-5-quinolyl group.

Examples of the benzodioxolyl lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 2 (preferably 1) benzodioxolyl groups. Specific examples thereof include a 2-, 4- or 5-(1,3-benzodioxolyl)methyl group, 2-(2-, 4- or 5-)(1,3-benzodioxolyl)ethyl group and 3-(2-, 4- or 5-)(1,3-benzodioxolyl) propyl group.

Examples of the aryl group that may have a group selected from the group consisting of a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have a group selected from the group consisting of a lower alkylsulfonyl group, lower alkyl group, and aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; lower alkynyl group; cyano group, nitro group; aryloxy group; aryl lower alkoxy group; hydroxy group; hydroxy lower alkyl group; carbamoyl group that may have a group selected from the group consisting of a lower alkyl group and an aryl group; pyrazolyl group; pyrrolidinyl group that may have an oxo group; oxazolyl group; imidazolyl group that may have a lower alkyl group; dihydrofuryl group that may have an oxo group; thiazolidinyl lower alkyl group that may have an oxo group; imidazolyl lower alkanoyl group; and piperidinylcarbonyl group include an aryl group as illustrated above that may have 1 to 7, preferably 1 to 5, more preferably, 1 to 2 groups, as a substituent(s), which are selected from the group consisting of

a halogen atom as illustrated above;

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms);

a halogen substituted lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 7 halogen atoms);

a halogen substituted lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with 1 to 7 halogen atoms);

a lower alkenyl group as illustrated above (preferably a linear or branched alkenyl group having 1 to 3 double bonds and 2 to 6 carbon atoms (including both trans and cis configurations));

an amino group having 1 to 2 lower alkanoyl groups as illustrated above, lower alkyl groups as illustrated above, and aryl groups as illustrated above;

a sulfamoyl group;

a lower alkylthio group whose lower alkyl moiety is a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms);

a lower alkoxycarbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms); a pyrrolyl group; an alkynyl group as illustrated below; cyano group; nitro group; aryloxy group whose aryl moiety is as illustrated above; aryl lower alkoxy group whose aryl moiety and lower alkoxy moiety are as illustrated above; hydroxy group; a hydroxy lower alkyl group whose lower alkyl moiety is as illustrated above; a carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group as illustrated above and aryl group as illustrated above; pyrazolyl group; pyrrolidinyl group that may have 1 to 2 (preferably 1) oxo groups; oxazolyl group; imidazolyl group that may have 1 to 3 (preferably 1 to 2) lower alkyl groups as illustrated above; dihydrofuryl group that may have 1 to 2 (preferably 1) oxo groups; thiazolidinyl group that may have 1 to 2 (preferably 1) oxo groups and having an lower alkyl moiety as illustrated above; imidazolyl lower alkanoyl group whose alkanoyl moiety is as illustrated above and piperidinylcarbonyl group. Specific examples thereof include a phenyl group, 1-naphthyl group, 2-naphthyl group, (2-, 3-, or 4-)biphenyl group, (2-, 3-, or 4-)chlorophenyl group, (2-, 3-, or 4-)fluorophenyl group, (2-, 3-, or 4-)bromophenyl group, (2-, 3-, or 4-)methylphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-1-naphthyl group, (2-, 3-, or 4-)n-propylphenyl group, (2-, 3-, or 4-)n-butylphenyl group, (2-, 3-, or 4-)n-pentylphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-1-naphthyl group, (2-, 3-, or 4-)isobutylphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-1-naphthyl group, (2-, 3-, or 4-)methoxyphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethoxy-1-naphthyl group, (2-, 3-, or 4-)n-propoxyphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)isopropoxy-1-naphthyl group, (2-, 3-, or 4-)n-butoxyphenyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutoxy-2-naphthyl group, (2-, 3-, or 4-)tert-butoxyphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)sec-butoxy-1-naphthyl group, (2-, 3-, or 4-)n-pentyloxyphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)isopentyloxy-1-naphthyl group, (2-, 3-, or 4-)neopentyloxyphenyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyloxy-2-naphthyl group, (2-, 3-, or 4-)isohexyloxyphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)(3-methylpentyloxy)-1-naphthyl group, (2-, 3-, or 4-)chloromethylphenyl group, (2-, 3-, or 4-)trifluoromethylphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoroethyl-1-naphthyl group, (2-, 3-, or 4-)(3-bromopropyl)phenyl group, (2-, 3-, or 4-)(4-chlorobutyl)phenyl group, (2-, 3-, or 4-)(5-fluoropentyl)phenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)(6-bromohexyl)-1-naphthyl group, (2-, 3-, or 4-)(1,1-dimethyl-2-chloroethyl)phenyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)(2-methyl-3-fluoropropyl)-2-naphthyl group, (2-, 3-, or 4-)chloromethoxyphenyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)(2-fluoroethoxy)-1-naphthyl group, (2-, 3-, or 4-)(3-bromopropoxy)phenyl group, (2-, 3-, or 4-)(4-chlorobutoxy)phenyl group, (2-, 3-, or 4-)(5-fluoropentyloxy)phenyl group, (2-, 3-, or 4-)trifluoromethoxyphenyl group, 4-(6-bromohexyloxy)-1-naphthyl group, (2-, 3-, or 4-)(1,1-dimethyl-2-chloroethoxy)phenyl group, 7-(2-methyl-3-fluoropropoxy)-2-naphthyl group, 2-vinylphenyl group, 2-(1-methylvinyl)phenyl group, 2-(1-propenyl)-1-naphthyl group, (2-, 3-, or 4-)(1-methyl-1-propenyl)phenyl group, 3-(2-methyl-1-propenyl)-1-naphthyl group, (2-, 3-, or 4-)(1-propenyl)phenyl group, (2-, 3-, or 4-)(2-propenyl)phenyl group, 4-(2-butenyl)-1-naphthyl group, (2-, 3-, or 4-)(1-butenyl)phenyl group, 5-(3-butenyl)-1-naphthyl group, (2-, 3-, or 4-)(2-pentenyl)phenyl group, 6-(1-pentenyl)-1-naphthyl group, (2-, 3-, or 4-)(3-pentenyl)phenyl group, 7-(4-pentenyl)-1-naphthyl group, (2-, 3-, or 4-)(1,3-butadienyl)phenyl group, 8-(1,3-pentadienyl)-1-naphthyl group, (2-, 3-, or 4-)(2-penten-4-ynyl)phenyl group, 1-(2-hexenyl)-2-naphthyl group, 4-(1-hexenyl)phenyl group, a 3-(5-hexenyl)-2-naphthyl group, (2-, 3-, or 4-)(3-hexenyl) group, 4-(4-hexenyl)-2-naphthyl group, (2-, 3-, or 4-)(3,3-dimethyl-1-propenyl)phenyl group, 5-(2-ethyl-1-propenyl)-2-naphthyl group, 4-(1,3,5-hexatrienyl)phenyl group, 6-(1,3-hexadienyl)-2-naphthyl group, (2-, 3-, or 4-)(1,4-hexadienyl)phenyl group, (2-, 3-, or 4-)(N-formylamino)phenyl group, (2-, 3-, or 4-)(N-acetylamino)phenyl group, 7-(N-acetylamino)-2-naphthyl group, (2-, 3-, or 4-)(N-propionylamino)phenyl group, 8-(N-butyrylamino)-2-naphthyl group, (2-, 3-, or 4-)(N-isobutyrylamino)phenyl group, 2-(N-pentanoylamino)-1-naphthyl group, (2-, 3-, or 4-)(N-tert-butylcarbonylamino)phenyl group, 3-(N-hexanoylamino)-1-naphthyl group, (2-, 3-, or 4-)(N,N-diformylamino)phenyl group, 4-(N,N-diacetylamino)-1-naphthyl group, (2-, 3-, or 4-)(N,N-dimethylamino)phenyl group, (2-, 3-, or 4-)(N-phenylamino)phenyl group, (2-, 3-, or 4-)sulfamoylphenyl group, 5-sulfamoyl-1-naphthyl group, (2-, 3-, or 4-)methylthiophenyl group, 6-ethylthio-1-naphthyl group, (2-, 3-, or 4-)n-propylthiophenyl group, 7-isopropylthio-1-naphthyl group, (2-, 3-, or 4-)n-butylthiophenyl group, 8-tert-butylthio-1-naphthyl group, (2-, 3-, or 4-)n-pentylthiophenyl group, 1-n-hexylthio-2-naphthyl group, (2-, 3-, or 4-)(N-methyl(sulfonylamino)phenyl group, (2-, 3-, or 4-)formylphenyl group, (2-, 3-, or 4-)acetylphenyl group, (2-, 3-, or 4-)butyrylphenyl group, 3-acetyl-2-naphthyl group, (2-, 3-, or 4-)propionylphenyl group, 4-butyryl-2-naphthyl group, (2-, 3-, or 4-)isobutyrylphenyl group, 5-pentanoyl-2-naphthyl group, (2-, 3-, or 4-)cyanophenyl group, (2-, 3-, or 4-)methoxycarbonylphenyl group, (2-, 3-, or 4-)tert-butylcarbonylphenyl group, 6-hexanoyl-2-naphthyl group, (2-, 3-, or 4-)ethoxycarbonylphenyl group, 7-ethoxycarbonyl-2-naphthyl group, (2-, 3-, or 4-)n-propoxycarbonylphenyl group, 8-isopropoxycarbonyl-2-naphthyl group, (2-, 3-, or 4-)n-butoxycarbonylphenyl group, 2-isobutoxycarbonyl-1-naphthyl group, (2-, 3-, or 4-)tert-butoxycarbonylphenyl group, 3-sec-butoxycarbonyl-1-naphthyl group, (2-, 3-, or 4-)n-pentyloxycarbonylphenyl group, 4-neopentyloxy-1-naphthyl group, (2-, 3-, or 4-)n-hexyloxycarbonylphenyl group, 5-isohexyloxycarbonyl-1-naphthyl group, (2-, 3-, or 4-) (3-methylpentyloxycarbonyl)phenyl group, 6-(1-pyrrolyl)-1-naphthyl group, (2-, 3-, or 4-)(1-pyrrolyl)phenyl group, (2-, 3-, or 4-)ethynylphenyl group, (2-, 3-, or 4-)(N-methylcarbamoyl)phenyl group, (2-, 3-, or 4-)(N-phenylcarbamoyl)phenyl group, (2-, 3-, or 4-)(2-hydroxyethyl)phenyl group, (2-, 3-, or 4-)phenoxyphenyl group, (2-, 3-, or 4-)nitrophenyl group, (2-, 3-, or 4-)benzyloxyphenyl group, (2-, 3-, or 4-)hydroxyphenyl group, (2-, 3-, or 4-)(2-oxo-2,5-dihydrofuran-4-yl)phenyl group, (2-, 3-, or 4-)(1-imidazolylacetyl)phenyl group, (2-, 3-, or 4-)(2,4-dioxothiazolidin-5-ylmethyl)phenyl group, (2-, 3-, or 4-)[(1-, 2-, 3-, or 4-)piperidylcarbonyl]phenyl group, (2-, 3-, or 4-)[(1-, 3-, 4-, or 5-)pyrazolyl]phenyl group, (2-, 3-, or 4-)[2-oxo-(1- or 3-)pyrrolidinyl]phenyl group, (2-, 3-, or 4-)[(2-, 4-, or 5-)oxazolyl]phenyl group, (2-, 3-, or 4-)(2-ethyl-4-methylimidazol-1-yl)phenyl group, (2-, 3-, or 4-) biphenyl group, 2,3-dimethoxyphenyl group, 2,4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 2-methoxy-5-chlorophenyl group, 2-methoxy-5-methylphenyl group, 2-methoxy-5-acetylaminophenyl group, 2-vinyl-4-methylphenyl group, 2-vinyl-5-ethylphenyl group, 2,6-disulfamoylphenyl group, 2,4,6-trimethoxyphenyl group, 3,4,5-triethoxyphenyl group, 2-vinyl-3,4,5-triethylphenyl group, pentamethoxyphenyl group, 2-vinylnaphthyl group, 2,3-dimethoxy-1-naphthyl group, 3,4-diethoxyphenyl group, 2-methoxy-5-methoxycarbonylphenyl group, 3,5-dimethoxycarbonylphenyl group, 3-chloro-4-hydroxyphenyl group, 2-chloro-5-(N-acetylamino)phenyl group, 2-chloro-5-cyanophenyl group, 2-chloro-5-carbamoylphenyl group, 2-methoxy-5-(N-acetylamino)phenyl group, 2-chloro-5-ethoxycarbonylphenyl group, 3,5,7-triethoxy-1-naphthyl group, 3,4,5,7-tetramethyl-1-naphthyl group, 2,3,4,5-tetramethyl-7-(N-pentaacetylamino)-1-naphthyl group, 2,3,4,5,6,7-hexaethoxy-1-naphthyl group, and heptamethoxy-1-naphthyl group.

Examples of the cyano lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having a single cyano group. Specific examples thereof include a cyanomethyl group, 2-cyanoethyl group, 1-cyanoethyl group, 3-cyanopropyl group, 4-cyanobutyl group, 1,1-dimethyl-2-cyanoethyl group, 5-cyanopentyl group, 6-cyanohexyl group, 1-cyanoisopropyl group, and 2-methyl-3-cyanopropyl group.

Examples of the lower alkanoylamino lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3, preferably 1, amino groups which has 1 to 2 lower alkanoyl groups as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms). Specific examples thereof include a 2-(N-formylamino)ethyl group, 2-(N-acetylamino)ethyl group, 2-(N-propionylamino) ethyl group, 2-(N-butyrylamino)ethyl group, 2-(N-isobutyrylamino)ethyl group, 2-(N-pentanoylamino)ethyl group, 2-(N-tert-butylcarbonylamino) ethyl group, 2-(N-hexanoylamino)ethyl group, N-acetylaminomethyl group, 1-(N-acetylamino)ethyl group, 3-(N-acetylamino)propyl group, 4-(N-acetylamino)butyl group, 5-(N-acetylamino)pentyl group, 6-(N-acetylamino)hexyl group, 1,1-dimethyl-2-(N-acetylamino)ethyl group, 2-methyl-3-(N-acetylamino)propyl group, and 2-(N,N-diacetylamino) ethyl group.

Examples of a halogen substituted lower alkylamino group include an amino group having 1 to 2 (preferably 1) halogen substituted lower alkyl groups as illustrated above (preferably a linear or branched halogen substituted alkyl group having 1 to 6 carbon atoms with 1 to 7 (preferably 1 to 3) halogen atoms). Specific examples thereof include an N-fluoromethylamino group, N-difluoromethylamino group, N-trifluoromethylamino group, N-chloromethylamino group, N-dichloromethylamino group, N-trichloromethylamino group, N-bromomethylaminogroup, N-dibromomethylamino group, N-dichlorofluoromethylamino group, N-2,2,2-trifluoroethylamino group, N-pentafluoroethylamino group, N-2-chloroethylamino group, N-3,3,3-trifluoropropylamino group, N-heptafluoropropylamino group, N-heptafluoroisopropylamino group, N-3-chloropropylamino group, N-2-chloropropylamino group, N-3-bromopropylamino group, N-4,4,4-trifluorobutylamino group, N-4,4,4,3,3-pentafluorobutylamino group, N-4-chlorobutylamino group, N-4-bromobutylamino group, N-2-chlorobutylamino group, N-5,5,5-trifluoropentylamino group, N-5-chloropentylamino group, N-6,6,6-trifluorohexylamino group, N-6-chlorohexylamino group, N-(1,1-dimethyl-2-chloroethyl)amino group, N-(2-methyl-3-fluoropropyl)amino group, and N,N-di(fluoromethyl)amino group.

Examples of the lower alkylthio lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3 lower alkylthio groups whose alkyl moiety is a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a 2-methylthioethyl group, 2-ethylthioethyl group, 2-n-propylthioethyl group, 2-n-butylthioethyl group, 2-tert-butylthioethyl group, 2-n-pentylthioethyl group, 2-n-hexylthioethyl group, methylthiomethyl group, 1-methylthioethyl group, 3-methylthiopropyl group, 4-methylthiobutyl group, 5-methylthiopentyl group, 6-methylthiohexyl group, 1,1-dimethyl-2-methylthioethyl group, 2-methyl-3-methylthiopropyl group, 2,2-diethylthioethyl group, and 2,2,2-triethylthioethyl group.

Examples of the amidino group that may have a lower alkyl group include an amidino group that may have 1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include an amidino group, N-methylamidino group, N-ethylamidino group, N-n-propylamidino group, N-n-butylamidino group, N-n-pentylamidino group, N-n-hexylamidino group, N-isopropylamidino group, N-tert-butylamidino group, N,N-dimethylamidino group, N,N′-dimethylamidino group, and N-methyl-N′-ethyl-amidino group.

Examples of the amidino lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3 amidino groups. Specific examples thereof include an amidinomethyl group, 2-amidinoethyl group, 3-amidinopropyl group, 4-amidinobutyl group, 5-amidinopropyl group, 6-amidinohexyl group, 1-amidinoethyl group, 1,1-dimethyl-2-amidinoethyl group, 2-methyl-3-amidinopropyl group, 2,2-diamidinoethyl group, and 2,2,2-triamidinoethyl group.

Examples of the lower alkenyloxy group include a lower alkenyloxy group whose lower alkenyl moiety is one as illustrated above (preferably a linear or branched alkenyloxy group having 1 to 3 double bonds and 2 to 6 carbon atoms). Specific examples thereof include a vinyloxy group, 1-propenyloxy group, 1-methyl-1-propenyloxy group, 2-methyl-1-propenyloxy group, 2-propenyloxy group, 2-butenyloxy group, 1-butenyloxy group, 3-butenyloxy group, 2-pentenyloxy group, 1-pentenyloxy group, 3-pentenyloxy group, 4-pentenyloxy group, 1,3-butadienyloxy group, 1,3-pentadienyloxy group, 2-penten-4-ynyloxy group, 2-hexenyloxy group, 1-hexenyloxy group, 5-hexenyloxy group, 3-hexenyloxy group, 4-hexenyloxy group, 3,3-dimethyl-1-propenyloxy group, 2-ethyl-1-propenyloxy group, 1,3,5-hexatrienyloxy group, 1,3-hexadienyloxy group, and 1,4-hexadienyloxy group.

Examples of the lower alkenyloxy lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3 lower alkenyloxy groups whose lower alkenyloxy moiety is a lower alkenyloxy group as illustrated above (preferably a linear or branched alkenyl group having 2 to 6 carbon atoms and 1 to 3 double bonds). Specific examples thereof include a vinyloxymethyl group, 2-vinyloxyethyl group, 2-(1-propenyloxy)ethyl group, 2-(1-methyl-1-propenyloxy)ethyl group, 2-(2-methyl-1-propenyloxy)ethyl group, 2-(2-propenyloxy)ethyl group, 2-(2-butenyloxy)ethyl group, 2-(1-butenyloxy)ethyl group, 2-(3-butenyloxy)ethyl group, 2-(2-pentenyloxy)ethyl group, 2-(1-pentenyloxy)ethyl group, 2-(3-pentenyloxy)ethyl group, 2-(4-pentenyloxy)ethyl group, 2-(1,3-butadienyloxy)ethyl group, 2-(1,3-pentadienyloxy)ethyl group, 2-(2-penten-4-ynyloxy)ethyl group, 2-(2-hexenyloxy)ethyl group, 2-(1-hexenyloxy)ethyl group, 2-(5-hexenyloxy)ethyl group, 2-(3-hexenyloxy)ethyl group, 2-(4-hexenyloxy)ethyl group, 2-(3,3-dimethyl-1-propenyloxy)ethyl group, 2-(2-ethyl-1-propenyloxy)ethyl group, 2-(1,3,5-hexatrienyloxy)ethyl group, 2-(1,3-hexadienyloxy)ethyl group, 2-(1,4-hexadienyloxy)ethyl group, 3-vinyloxypropyl group, 4-vinyloxybutyl group, 5-vinyloxypropyl group, 6-vinyloxyhexyl group, 1-vinyloxyethyl group, 1,1-dimethyl-2-vinyloxyethyl group, 2-methyl-3-vinyloxypropyl group, 2,2-divinyloxyethyl group, and 2,2,2-trivinyloxyethyl group.

Examples of the arylamino group that may have a substituent selected from the group consisting of a lower alkyl group, lower alkoxy group, halogen substituted lower alkyl group, and halogen substituted lower alkoxy group on the aryl group include an amino group having 1 to 2 aryl groups as illustrated above that may have 1 to 7, preferably 1 to 5, more preferably 1 to 2 substituents, on the aryl group, which are selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms);

a halogen substituted alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms with 1 to 7, preferably 1 to 3 halogen atoms); and

halogen substituted lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms with 1 to 7, preferably 1 to 3 halogen atoms). Specific examples thereof include an N-phenylamino group, N-2-naphthylamino group, N-(2-methylphenyl)amino group, N-(3-ethyl-1-naphthyl)amino group, N-(4-n-propylphenyl)amino group, N-(2-n-butyl-1-phenyl)amino group, N-(3-n-pentylphenyl)amino group, N-(4-n-hexyl-1-naphthyl)amino group, N-(2-isobutylphenyl)amino group, N-(3-tert-butyl-1-naphthyl)amino group, N-(2-methoxyphenyl)amino group, N-(3-ethoxy-1-naphthyl)amino group, N-(4-n-propoxyphenyl)amino group, N-(3-isopropoxy-1-naphthyl)amino group, N-(n-butoxyphenyl)amino group, N-(1-isobutoxy-2-naphthyl)amino group, N-(tert-butoxyphenyl)amino group, N-(5-sec-butoxy-1-naphthyl)amino group, N-(n-pentyloxyphenyl)amino group, N-(5-isopentyloxy-1-naphthyl)amino group, N-(1-neopentyloxyphenyl)amino group, N-(6-n-hexyloxy-2-naphthyl)amino group, N-(isohexyloxyphenyl)amino group, N-(3-methylpentyloxy-1-naphthyl)amino group, N-(2-trifluoromethylphenyl)amino group, N-(4-trifluoromethylphenyl)amino group, N-(2-chloromethylphenyl)amino group, N-[3-(2-fluoroethyl)-1-naphthyl]amino group, N-[4-(3-bromopropyl)phenyl]amino group, N-[2-(4-chlorobutyl)-1-phenyl]amino group, N-[3-(5-fluoropentyl)phenyl]amino group, N-[4-(6-bromohexyl)-1-naphthyl]amino group, N-[2-(1,1-dimethyl-2-chloroethyl)phenyl]amino group, N-[7-(2-methyl-3-fluoropropyl)-2-naphthyl]amino group, N-(2-chloromethoxyphenyl)amino group, N-(4-trifluoromethoxyphenyl)amino group, N-(3-(2-fluoroethoxy)-1-naphthyl)amino group, N-[4-(3-bromopropoxy)phenyl]amino group, N-[2-(4-chlorobutoxy)-1-phenyl]amino group, N-[3-(5-fluoropentyloxy)phenyl]amino group, N-[4-(6-bromohexyloxy)-1-naphthyl]amino group, N-[2-(1,1-dimethyl-2-chloroethoxy)phenyl]amino group, N-[7-(2-methyl-3-fluoropropoxy)-2-naphthyl]amino group, N-(2-chloromethoxyphenyl)amino group, N-[3-(2-fluoroethoxy)-1-naphthyl]amino group, N-[4-(3-bromopropoxy)phenyl]amino group, N-[2-(4-chlorobutoxy)-1-phenyl]amino group, N-[3-(5-fluoropentyloxy)phenyl]amino group, N-[4-(6-bromohexyloxy)-1-naphthyl]amino group, N-[2-(1,1-dimethyl-2-chloroethoxy)phenyl]amino group, N-[7-(2-methyl-3-fluoropropoxy)-2-naphthyl]amino group, and N,N-diphenylamino group.

Examples of the aryl lower alkenyl group include a lower alkenyl group as illustrated above having an aryl group as illustrated above (preferably a linear or branched alkenyl group having 1 to 3 aryl groups and 1 to 6 carbon atoms). Specific examples thereof include a 2-phenylethenyl group, 3-phenyl-2-propenyl group, 3-[(1- or 2-)naphthyl]-2-propenyl group, 4-[(2-, 3-, or 4-)methylphenyl]-2-butenyl group, 4-[(2-, 3-, or 4-)ethylphenyl]-3-butenyl group, 4-[(2-, 3-, or 4-)n-propylphenyl]-1,3-butadienyl group, 5-[(2-, 3-, or 4-)n-butylphenyl]-1,3,5-hexatrienyl group, 5-[(2-, 3-, or 4-)n-pentylphenyl]-2,4-hexadienyl group, 5-[(2-, 3-, or 4-)n-hexylphenyl]-3-pentenyl group, 3-[(2-, 3-, or 4-)isobutylphenyl]-2-propenyl group, 2-[(2-, 3-, or 4-)tert-butylphenyl]phenyl group, 3-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-1-naphthyl]-2-propenyl group, 4-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-2-naphthyl]-2-butenyl group, 4-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-1-naphthyl]-3-butenyl group, 4-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-2-naphthyl]-1,3-butadienyl group, 5-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-1-naphthyl]-1,3,5-hexatrienyl group, 5-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-2-naphthyl]-2,4-hexadienyl group, 5-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-1-naphthyl]-3-pentenyl group, 3-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-2-naphthyl]-2-propenyl group, 2-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-1-naphthyl]ethenyl group, 3-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-2-naphthyl]-2-propenyl group, 4-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-1-naphthyl]-2-butenyl group, 4-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-2-naphthyl]-3-butenyl group, 4-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-1-naphthyl]-1,3-butadienyl group, 5-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-2-naphthyl]-1,3,5-hexatrienyl group, 5-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-1-naphthyl]-2,4-hexadienyl group, 5-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-2-naphthyl]-1,3,5-hexatrienyl group, 5-[(2-, 3-, or 4-)chlorophenyl group, (2-, 3-, or 4-)fluorophenyl]-2,4-hexadienyl group, 5-[(2-, 3-, or 4-)bromophenyl]-3-pentenyl group, 3-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-1-naphthyl]-2-propenyl group, 2-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-2-naphthyl]ethenyl group, 3-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-1-naphthyl]-2-propenyl group, 4-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-2-naphthyl]-2-butenyl group, 4-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-1-naphthyl]-3-butenyl group, 4-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-2-naphthyl]-1,3-butadienyl group, 5-[(2-, 3-, or 4-)aminophenyl]-1,3,5-hexatrienyl group, 5-[(2-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-1-naphthyl]-2,4-hexadienyl group, 5-[(1-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-2-naphthyl]-3-pentenyl group, 3-(2,3-dimethylphenyl)-2-propenyl group, 2-(3,4-dimethylphenyl)vinyl group, 3-(2,4-dimethylphenyl)-2-propenyl group, 4-(2,5-dimethylphenyl)-2-butenyl group, 4-(2,6-dimethylphenyl)-3-butenyl group, 4-(2,4,6-trimethylphenyl)-1,3-butadienyl group, 5-(3,4,5-trimethylphenyl)-1,3,5-hexatrienyl group, 5-(2,3,4,5-tetraethylphenyl)-2,4-hexadienyl group, 5-(pentamethylphenyl)-3-pentenyl group, 3-(2-methylnaphthyl)-2-propenyl group, 2-(2,3-dimethylnaphthyl)ethenyl group, 3-(3,4-dimethylphenyl)-2-propenyl group, 4-(3,5,7-triethylnaphthyl)-2-butenyl group, 4-(3,4,5,7-tetramethylnaphthyl)-3-butenyl group, 4-(2,3,4,5,7-pentamethylnaphthyl)-1,3-butadienyl group, 5-(2,3,4,5,6,7-hexaethylnaphthyl)-1,3,5-hexatrienyl group, 5-(heptamethylnaphthyl)-2,4-hexadienyl group, 5-(2,3-diaminophenyl)-3-pentenyl group, 3-(2,4,6-triaminophenyl)-2-propenyl group, and 2-(2-methyl-5-chloronaphthyl)ethenyl group.

Examples of the pyridylamino group that may have a lower alkyl group include a pyridylamino group that may have 1 to 3, preferably 1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms), on the pyridyl group and/or amino group. Specific examples thereof include an N-(2-, 3-, or 4-)pyridylamino group, N-3-methyl-2-pyridylamino group, N-(4-methyl-2-pyridyl)amino group, N-(5-methyl-2-pyridyl)amino group, N-(6-methyl-2-pyridyl)amino group, N-(2-methyl-3-pyridyl)amino group, N-(4-methyl-3-pyridyl)amino group, N-(5-methyl-3-pyridyl)amino group, N-(6-methyl-3-pyridyl)amino group, N-(2-methyl-4-pyridyl)amino group, N-(3-methyl-4-pyridyl)amino group, N-(3-ethyl-2-pyridyl)amino group, N-(4-n-propyl-2-pyridyl)amino group, N-(5-n-propyl-2-pyridyl)amino group, N-(2-n-butyl-3-pyridyl)amino group, N-(4-n-pentyl-3-pyridyl)amino group, N-(5-n-hexyl-3-pyridyl)amino group, N-(2-isopropyl-4-pyridyl)amino group, N-(3-tert-butyl-4-pyridyl)amino group, N-(3-methyl-2-pyridyl)-N-methyl-amino group, and N-(2,4-diethyl-3-pyridyl)-N-methyl-amino group.

Examples of the aryl lower alkyl group (that may have a group selected from the group consisting of halogen atom, lower alkyl group, halogen substituted alkyl group, halogen substituted lower alkoxy group, lower alkoxy group, carbamoyl group, and lower alkoxycarbonyl group, as a substituent, on the aryl group and/or the lower alkyl group) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 3 (preferably 1) aryl groups as illustrated above. Note that, on the aryl group and/or the alkyl moiety, there may be 1 to 7, preferably 1 to 5, more preferably, 1 to 2 substituents selected from the group consisting of

a halogen atom as illustrated above;

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a halogen substituted lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 7 halogen atoms);

a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with 1 to 7 halogen atoms);

a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms);

a carbamoyl group; and

a lower alkoxy-carbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms). Specific examples of the aryl lower alkyl group (that may have a substituent selected from the group consisting of a halogen atom, lower alkyl group, halogen substituted lower alkyl group, halogen substituted lower alkoxy group, lower alkoxy group, carbamoyl group and lower alkoxycarbonyl group, on the aryl group and/or the lower alkyl group) include a benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-methyl-1-phenylethyl group, 1,1-dimethyl-2-phenylethyl group, 1,1-dimethyl-3-phenylpropyl group, (2-, 3-, or 4-)fluorobenzyl group, 2-[(2-, 3-, or 4-)fluorophenyl]ethyl group, 1-[(2-, 3-, or 4-)fluorophenyl]ethyl group, 1-[(2-, 3-, or 4-) fluorophenyl]propyl group, 2-[(2,6- or 3,5-) difluorophenyl]ethyl group, 1-(3,5-difluorophenyl)ethyl group, 1-(3,5-difluorophenyl)propyl group, (2-, 3-, or 4-)chlorobenzyl group, 2-[(2-, 3-, or 4-)chlorophenyl]ethyl group, 2-(3,4-dichlorophenyl)ethyl group, 1-(3-chlorophenyl)butyl group, 1-(4-chlorophenyl)butyl group, (2-, 3-, or 4-)trifluoromethylphenylbenzyl group, 1-[(2-, 3-, or 4-)trifluoromethylphenyl]ethyl group, 1-[(2-, 3-, or 4-)trifluoromethylphenyl]propyl group, (2-, 3-, or 4-)methylbenzyl group, 2-[(2- 3-, or 4-)methylphenyl]ethyl group, (2-, 3-, or 4-)trifluoromethoxybenzyl group, 1-[(2-, 3-, or 4-)trifluoromethylphenyl]ethyl group, (2-, 3-, or 4-)methoxybenzyl group, 2-[(2-, 3-, or 4-)methylphenyl]ethyl group, 1-[(2-, 3-, or 4-)methoxyphenyl]propyl group, (2-, 3-, or 4-)ethoxybenzyl group, (3,4- or 3,5-)dimethoxybenzyl group, (3,4- or 3,5-)di(n-butoxy)benzyl group, 2-[(3,5- or 3,4-)dimethoxyphenyl]ethyl group, 2-(2-ethoxyphenyl)ethyl group, 1-(4-methoxyphenyl)butyl group, 1-phenyl-1-methoxycarbonylmethyl group, 1-carbamoyl-2-phenylethyl group, 1-methoxycarbonyl-2-phenylethyl group, 2-methoxycarbonyl-2-phenylethyl group, 2-phenyl-2-hydroxyethyl group, 2-(4-hydroxyphenyl)-1-methoxycarbonylethyl group, 3-chloro-4-difluoromethoxyphenylmethyl group, and naphthylmethyl group.

Examples of the lower alkynyl group include a linear or branched alkynyl group having 2 to 6 carbon atoms. Specific examples thereof include an ethynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, and 2-hexynyl group.

Examples of the aryloxy lower alkyl group (on the aryl group, a group selected from the group consisting of a lower alkoxy group; a carbamoyl group that may have a group selected from the group consisting of a lower alkoxy group and a lower alkyl group; and a pyrrolidinyl group that may have an oxo group, may be present, include an aryl lower alkyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) whose aryl moiety and lower alkyl group are as illustrated above. On the aryl group herein, 1 to 5 (preferably 1 to 2) groups selected from the group consisting of a lower alkoxy group as illustrated above; a carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkoxy group as illustrated above and a lower alkyl group as illustrated above; and oxo group may be present as a substituent(s). Specific examples thereof include a 2-[(2-, 3- or 4-)methoxyphenoxy]ethyl group, 2-[(2-, 3- or 4-)carbamoylphenoxy]ethyl group, 2-[(2-, 3- or 4-)(N-methyl-N-ethoxycarbamoyl)phenoxy]ethyl group and 2-[(2-, 3- or 4-)(2-oxo-1-pyrrolidinyl)phenoxy]ethyl group.

Examples of the isoxazolidinyl group that may have an oxo group include an isoxazolidinyl group that may have 1 to 2 (preferably 1) oxo groups. Specific examples thereof include a 3-oxoisooxazolidin-4- or 5-yl group and 3,5-dioxoisoxazolidin-4-yl group.

Examples of the dihydroindenyl group include a (1-, 2-, 4- or 5-)-1,2-dihydroindenyl group.

Examples of the aryl lower alkoxy lower alkyl group include an aryl lower alkoxy lower alkyl group whose aryl moiety, lower alkoxy moiety and lower alkyl group moiety are as illustrated above. Specific examples thereof include a benzyloxymethyl group, 2-benzyloxyethyl group and 2-benzyloxybutyl group.

Examples of the azetidinyl group that may have a group selected from the group consisting of a lower alkanoyl group and an aroyl group include an azetidinyl group that may have a 1 to 3 (preferably 1) groups selected from a lower alkanoyl group as illustrated above and an aroyl group as illustrated above. Specific examples thereof include a 2- or 3-azetinyl group, 1-acetyl-(2- or 3-)azetidinyl group, 1-butyryl-(2- or 3-)azetidinyl group and 1-benzoyl-(2- or 3-)azetidinyl group.

Examples of the azetidinyl lower alkyl group that may have a group selected from the group consisting of a lower alkanoyl group and an aroyl group include an azetidinyl lower alkyl group that may have 1 to 3 (preferable 1) groups selected from the group consisting of a lower alkanoyl group as illustrated above and an aroyl group as illustrated above and have a lower alkyl moiety as illustrated above. Specific examples thereof include a 2- or 3-azetidinylmethyl group, 2-(2- or 3-azetidinyl)ethyl group, 1-acetyl-(2- or 3-)azetidinylmethyl group, 1-butyryl-(2- or 3-)azetidinylmethyl group, 1-benzoyl-(2- or 3-)azetidinylmethyl group, 2-[1-acetyl-(2- or 3-)azetidinyl]ethyl group, 2-[1-butyryl-(2- or 3-)azetidinyl]ethyl group and 2-[1-benzoyl-(2- or 3-)azetidinyl]ethyl group.

Examples of the tetrazolyl group include a (1- or 5-)tetrazolyl group.

Examples of the indolinyl group that may have an oxo group include an indolinyl group that may have 1 to 2 (preferably 1) oxo groups. Specific examples thereof include a (1-, 3-, 5-, 6-, 7- or 8-)indolinyl group, 2-oxo-(1-, 3-, 5-, 6-, 7- or 8-)indolinyl group and 2,3-dioxo-(1-, 5-, 6-, 7- or 8-)indolinyl group.

Examples of the triazolyl group include a 1,2,4,-trizolyl group and a 1,3,5,-trizolyl group.

Examples of the triazolyl group that may have a group selected from the group consisting of a lower alkyl group and a lower alkylthio group include a triazolyl group as illustrated above that may have 1 to 3 (more preferably 1 to 2) groups selected from the group consisting of a lower alkyl group as illustrated above and a lower alkylthio group as illustrated above. Specific examples thereof include a (1-, 3- or 5-)-1,2,4-triazolyl group, (1-, 2- or 5-)-1,3,5-triazolyl group, 1-methyl-5-methylthio-1,2,4-triazol-3-yl group and 1-methyl-5-methylthio-1,2,3-triazol-2-yl group.

Examples of the imidazolyl group that may have a carbamoyl group include an imidazolyl group that may have 1 to 2 (preferably 1) carbamoyl groups. Specific examples thereof include a (1-, 2-, 4- or 5-) imidazolyl group and a 4-carbamoyl-(1,2- or 5-) imidazolyl group.

Examples of the oxazolyl group that may have a lower alkyl group include an oxazolyl group that may have 1 to 2 (preferably 1) lower alkyl groups as illustrated above. Specific examples thereof include a (2-, 3- or 4-)oxazolyl group and a 4-methyl-(2- or 3-)oxazolyl group.

Examples of the isothiazolyl group that may have a lower alkyl group include an isothiazolyl group that may have 1 to 2 (preferably 1) lower alkyl groups as illustrated above. Specific examples thereof include a (3-, 4- or 5-)isothiazolyl group and a (3- or 4-)methyl-2-isothiazolyl group.

Examples of the dihydrobenzothiazolyl group include a (1-, 2-, 4-, 5-, 6- or 7-)2,3-dihydrobenzothiazolyl group.

Examples of the dihydrobenzothiazolyl group that may have an oxo group include a dihydrobenzothiazolyl group that may have a single oxo group. Specific examples thereof include a (1-, 2-, 5-, 6-, 7- or 8-)2,3-dihydrobenzothiazolyl group and a 2-oxo-(1-, 5-, 6-, 7- or 8-)2,3-dihydrobenzothiazolyl group.

Examples of the thienyl group that may have a lower alkoxycarbonyl group include a thienyl group that may have 1 to 2 (preferably 1) lower alkoxycarbonyl groups as illustrated above. Specific examples thereof include a (2- or 3-)thienyl group and a 3-methoxycarbonyl-2-thienyl group.

Examples of the oxazolyl lower alkyl group that may have a lower alkyl group include an oxazolyl lower alkyl group as illustrated above, whose alkyl group as illustrated above, having 1 to 3 (more preferably 1 to 2) lower alkyl groups as illustrated above on the oxazole ring. Specific examples thereof include a (2-, 4- or 5-)oxazolylmethyl group, 2-(2-, 4- or 5-)oxazolylmethyl group, [2-methyl-(4- or 5-)oxazolyl]methyl group and (2,5-dimethyl-4-oxazolyl)methyl group.

Examples of the amino lower alkyl group that may have a group, on the amino group, which is selected from the group consisting of a lower alkyl group, halogen substituted lower alkyl group, lower alkoxycarbonyl group, lower alkanoyl group, aryl group, aryl lower alkyl group, aroyl group, and amino substituted alkyl group (on the amino group of the amino substituted alkyl group, a lower alkyl group may be present as a substituent) include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 5, preferable 1 to 3, more preferably 1, amino groups. Note that, on the amino group, 1 to 2 substituents may be present which are selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a halogen substituted lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms with 1 to 13, preferably 1 to 7, more preferably 1 to 3 halogen atoms);

a lower alkoxy-carbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms);

a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms);

an aryl group as illustrated above;

an aryl lower alkyl group as illustrated above;

an aroyl group as illustrated above; and

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) having 1 to 5, preferably 1 to 3, more preferably 1, amino groups (1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present on the amino group, as a substituent(s)). Specific examples of the amino lower alkyl group that may have, on the amino group, a group selected from the group consisting of a lower alkyl group, halogen substituted lower alkyl group, lower alkoxycarbonyl group, lower alkanoyl group, aryl group, aryl lower alkyl group, aroyl group, and amino substituted alkyl group ((on the amino group of the amino substituted alkyl group, a lower alkyl group may be present as a substituent) include an N-methylaminomethyl group, N-ethylaminomethyl group, N-n-propylaminomethyl group, N,N-dimethylaminomethyl group, N,N-diethylaminomethyl group, N-methyl-N-n-propylaminomethyl group, N-methyl-N-ethylaminomethyl group, N-(2,2,2-trifluoroethyl)aminomethyl group, N-methyl-N-benzylaminomethyl group, N-phenylaminomethyl group, N-methyl-N-phenylaminomethyl group, N-formylaminomethyl group, N-methyl-N-acetylaminomethyl group, N-methyl-N-propionylaminomethyl group, N-(2-(N,N-diethylamino)ethyl)aminomethyl group, N-methyl-N-benzoylaminomethyl group, N-methylaminoethyl group, N-ethylaminoethyl group, N-(2,2,2-trifluoroethyl)aminoethyl group, N,N-dimethylaminoethyl group, N,N-diethylaminoethyl group, N-methyl-N-acetylaminoethyl group, N-methyl-N-benzoylaminoethyl group, N-methyl-N-propionylaminoethyl group, N-methyl-N-benzylaminoethyl group, and N-methyl-N-tert-butoxycarbonylaminoethyl group.

Examples of the lower alkyl group substituted with a carbamoyl group that may have a group selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group include a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) and substituted with 1 to 3 (preferably 1) carbamoyl groups that may have 1 to 2 groups selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms); and

a halogen substituted lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms and 1 to 13, preferably 1 to 7, more preferably 1 to 3 halogen atoms). Specific examples thereof include a carbamoylmethyl group, 2-carbamoylethyl group, 1-carbamoylethyl group, 3-carbamoylpropyl group, 4-carbamoylbutyl group, 5-carbamoylpentyl group, 6-carbamoylhexyl group, 1,1-dimethyl-2-carbamoylethyl group, 2-methyl-3-carbamoylpropyl group, 1,2-dicarbamoylethyl group, 2,2-dicarbamoylethyl group, 1,2,3-tricarbamoylpropyl group, N-methylcarbamoylmethyl group, N-ethylcarbamoylmethyl group, 2-(N-n-propylcarbamoyl)ethyl group, 3-(N-n-butylcarbamoyl)propyl group, 4-(N-isobutylcarbamoyl)butyl group, 5-(N-tert-butylcarbamoyl)pentyl group, 6-(N-pentylcarbamoyl)hexyl group, N,N-dimethylcarbamoylmethyl group, N,N-diethylcarbamoylmethyl group, 2-(N-2-fluoroethylcarbamoyl)ethyl group, 3-(N-2-chloroethylcarbamoyl)propyl group, 4-(N-2-bromoethylcarbamoyl)butyl group, 2-(N-2,2-dichloroethylcarbamoyl)ethyl group, N-2,2,2-trifluoroethylcarbamoylmethyl group, and N-heptafluoropropylcarbamoylmethyl group.

Examples of the thiocarbamoyl group that may have a lower alkyl group include a thiocarbamoyl group that may have 1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a thiocarbamoyl group, N-methyl-thiocarbamoyl group, N-ethyl-thiocarbamoyl group, N-n-propyl-thiocarbamoyl group, N-n-butyl-thiocarbamoyl group, N-n-pentyl-thiocarbamoyl group, N-n-hexyl-thiocarbamoyl group, N-isobutyl-thiocarbamoyl group, N-tert-butyl-thiocarbamoyl group, N,N-dimethyl-thiocarbamoyl group, and N-methyl-N-ethyl-thiocarbamoyl group.

Examples of the oxazolidinyl group that may have an oxo group include an oxazolidinyl group that may have 1 to 2 (preferably 1) oxo groups. Specific examples thereof include an oxazolidin-3-yl group, oxazolidin-4-yl group, oxazolidin-5-yl group, 2-oxo-oxazolidin-4-yl group, 2-oxo-oxazolidin-3-yl group, and 2-oxo-oxazolidin-5-yl group.

Examples of the imidazolidinyl group that may have a substituent selected from the group consisting of an oxo group and a lower alkyl group include an imidazolidinyl group that may have 1 to 3, preferably 1 to 2 substituents selected from the group consisting of oxo group and a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include an imidazolidin-1-yl group, imidazolidin-2-yl group, imidazolidin-4-yl group, 2-oxo-imidazolidin-1-yl group, 4-oxo-imidazolidin-1-yl group, 5-oxo-imidazolidin-1-yl group, 4-oxo-imidazolidin-2-yl group, 2-oxo-imidazolidin-4-yl group, 2-methyl-imidazolidin-1-yl group, 4-ethyl-imidazolidin-1-yl group, 5-n-propyl-imidazolidin-1-yl group, 4-n-butyl-imidazolidin-2-yl group, 2-n-pentyl-imidazolidin-4-yl group, 2-n-hexyl-imidazolidin-1-yl group, 4-isobutyl-imidazolidin-2-yl group, 2-tert-butyl-imidazolidin-4-yl group, 2-oxo-3-methyl-imidazolidin-1-yl group, and 2-oxo-3,4-dimethyl-imidazolidin-1-yl group.

Examples of the pyrrolidinyl group that may have an oxo group include a pyrrolidinyl group that may have 1 to 2 (preferably 1) oxo groups. Specific examples thereof include a (1-, 2- or 3-)pyrrolidinyl group, (2- or 3-)oxo-1-pyrrolidinyl group, (3-, 4- or 5-)oxo-2-pyrrolidinyl group, and (2-, 4- or 5-)oxo-3-pyrrolidinyl group.

Examples of the imidazolyl group include a (1-, 2-, 4- or -5)imidazolyl group.

Examples of the isoxazolyl group include a (3-, 4- or 5-)isoxazolyl group.

Examples of the arylsulfonyl group include an arylsulfonyl group whose aryl moiety is phenyl, biphenyl, substituted biphenyl, substituted phenyl, naphthyl and substituted naphthyl, and which may have, on the aryl moiety, 1 to 7, preferably 1 to 5, more preferably 1 to 2 linear or branched alkyl groups having 1 to 6 carbon atoms. Examples of the substituent such as phenyl, biphenyl and naphthyl include a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, an amino group and the like. One to seven, preferably 1 to 5, more preferably 1 to 2 substituents of at least one type of these may be present on the phenyl, biphenyl, naphthyl ring and the like. Specific Examples of the arylsulfonyl group that may have a lower alkyl group on the aryl group include a phenylsulfonyl group, (2-, 3-, or 4-) biphenylsulfonyl group, (1- or 2-)naphthylsulfonyl group, (2-, 3-, or 4-)methylphenylsulfonyl group, (2-, 3-, or 4-)ethylphenylsulfonyl group, (2-, 3-, or 4-n-propylphenylsulfonyl group, (2-, 3-, or 4-)n-butylphenylsulfonyl group, (2-, 3-, or 4-)n-pentylphenylsulfonyl group, (2-, 3-, or 4-)n-hexylphenylsulfonyl group, (2-, 3-, or 4-)isobutylphenylsulfonyl group, (2-, 3-, or 4-)tert-butylphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)methyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)ethyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-propyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-butyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-pentyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)n-hexyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)isobutyl-4-biphenylsulfonyl group, (3-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-2-biphenylsulfonyl group, (2-, 4-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-3-biphenylsulfonyl group, (2-, 3-, 5-, 6-, 2′-, 3′-, 4′-, 5′-, or 6′-)tert-butyl-4-biphenylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)methyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)ethyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-propyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-butyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-pentyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)n-hexyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)isobutyl-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)tert-butyl-2-naphthylsulfonyl group, (2-, 3-, or 4-)chlorophenylsulfonyl group, (2-, 3-, or 4-)fluorophenylsulfonyl group, (2-, 3-, or 4-)bromophenylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)chloro-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)fluoro-2-naphthylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)bromo-2-naphthylsulfonyl group, (2-, 3-, or 4-)aminophenylsulfonyl group, (2-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-1-naphthylsulfonyl group, (1-, 3-, 4-, 5-, 6-, 7-, or 8-)amino-2-naphthylsulfonyl group, 2,3-dimethylphenylsulfonyl group, 3,4-dimethylphenylsulfonyl group, 2,4-dimethylphenylsulfonyl group, 2,5-dimethylphenylsulfonyl group, 2,6-dimethylphenylsulfonyl group, 2,4,6-trimethylphenylsulfonyl group, 3,4,5-trimethylphenylsulfonyl group, 2,3,4,5-tetraethylphenylsulfonyl group, pentamethylphenylsulfonyl group, 2-methylnaphthylsulfonyl group, 2,3-dimethylnaphthylsulfonyl group, 3,4-dimethylphenylsulfonyl group, 3,5,7-triethylnaphthylsulfonyl group, 3,4,5,7-tetramethylnaphthylsulfonyl group, 2,3,4,5,7-pentamethylnaphthylsulfonyl group, 2,3,4,5,6,7-hexaethylnaphthylsulfonyl group, heptamethylnaphthylsulfonyl group, 2,3-diaminophenylsulfonyl group, 2,4,6-triaminophenylsulfonyl group, and 2-methyl-5-chloronaphthylsulfonyl group.

Examples of the piperidyl group that may have a substituent selected from the group consisting of a lower alkyl group; lower alkanoyl group; arylsulfonyl group; oxo group; hydroxy group and amino group that may have a group selected from the group consisting of a lower alkyl group, lower alkanoyl group, lower alkoxycarbonyl group and lower alkanoylamino lower alkanoyl group include a piperidyl group that may have 1 to 5, preferably 1 to 3, more preferably 1 substituent selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms); and

an arylsulfonyl group as illustrated above; an oxo group; a hydroxy group; and an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group as illustrated above, lower alkanoyl group as illustrated above, lower alkoxycarbonyl group as illustrated above and lower alkanoyl amino lower alkanoyl group as illustrated above. Specific examples thereof include a (1-, 2-, 3-, or 4-)piperidyl group, 1-methyl-4-piperidyl group, 2-ethyl-4-piperidyl group, 3-n-propyl-4-piperidyl group, 4-isopropyl-4-piperidyl group, 2-n-butyl-1-piperidyl group, 3-isobutyl-1-piperidyl group, 4-tert-butyl-1-piperidyl group, 1-sec-butyl-2-piperidyl group, 2-n-pentyl-2-piperidyl group, 3-(1-ethylpropyl)-2-piperidyl group, 4-iso-pentyl-2-piperidyl group, 5-neopentyl-2-piperidyl group, 6-n-hexyl-2-piperidyl group, 1-(1,2,2-trimethylpropyl)-3-piperidyl group, 2-(3,3-dimethylbutyl)-3-piperidyl group, 3-(2-ethylbutyl)-3-piperidyl group, 4-isohexyl-3-piperidyl group, 5-(3-methylpentyl group)-3-piperidyl group, 6-formyl-3-piperidyl group, 1-acetyl-4-piperidyl group, 2-propionyl-4-piperidyl group, 3-butyryl-4-piperidyl group, 4-isobutyryl-4-piperidyl group, 2-pentanoyl-1-piperidyl group, 3-tert-butylcarbonyl-1-piperidyl group, 4-hexanoyl-1-piperidyl group, 1-phenylsulfonyl-2-piperidyl group, 2-(2-biphenylsulfonyl)-2-piperidyl group, 3-(1-naphthylsulfonyl)-2-piperidyl group, 1-tosyl-4-piperidyl group, 4-(4-ethylphenylsulfonyl)-2-piperidyl group, 5-(2-n-propylphenylsulfonyl)-2-piperidyl group, 6-(3-n-butylphenylsulfonyl)-2-piperidyl group, 1-(4-n-pentylphenylsulfonyl)-3-piperidyl group, 2-(2-n-hexylphenylsulfonyl)-3-piperidyl group, 3-(3-isobutylphenylsulfonyl)-3-piperidyl group, 4-(4-tert-butylphenylsulfonyl)-3-piperidyl group, 5-(2-chlorophenylsulfonyl)-3-piperidyl group, 6-(4-fluorophenylsulfonyl)-3-piperidyl group, 1-(3-bromophenylsulfonyl)-4-piperidyl group, 2-(2-aminophenylsulfonyl)-4-piperidyl group, 3-(2,3-dimethylphenylsulfonyl)-4-piperidyl group, 4-(3,4,5-trimethylphenylsulfonyl)-4-piperidyl group, 2-(2,3-diaminophenylsulfonyl)-1-piperidyl group, 4-oxo-1-piperidyl group, 2-oxo-3-piperidyl group, 4-hydroxy-1-piperidyl group, 2-hydroxy-3-piperidyl group, 4-amino-1-piperidyl group, 2-amino-4-piperidyl group, 4-methylamino-1-piperidyl group, 2-methylamino-4-piperidyl group, 4-ethylamino-1-piperidyl group, 2-ethylamino-4-piperidyl group, 2-dimethylamino-4-piperidyl group, 4-diethylamino-1-piperidyl group, 4-formylamino-1-piperidyl group, 4-acetylamino-1-piperidyl group, 4-(N-methyl-N-acetylamino)-1-piperidyl group, 4-(N-methyl-N-methoxycarbonylamino)-1-piperidyl group, 4-(N-methyl-N-tert-butoxycarbonylamino)-1-piperidyl group, 4-[N-methyl-N—(N-acetylamino)acetylamino]-1-piperidyl group.

Examples of the piperidylcarbonyl group that may have a substituent selected from the group consisting of

a lower alkyl group, hydroxy group, hydroxy lower alkyl group, lower alkanoyl group, carboxy lower alkyl group, lower alkyl carbamoyl lower alkyl group, carbamoyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, lower alkanoyl group, lower alkoxycarbonyl group and aroyl group may be present), piperidyl group (on which a group selected from the group consisting of a lower alkanoyl group, lower alkoxycarbonyl group and aroyl group may be present), piperazinyl group (on which a lower alkyl group may be present as a substituent), 1,4-dioxa-8-azasprio[4.5]decyl group, morpholinyl group, hexahydro-1,4-diazepinyl group (on which a lower alkyl group may be present as a substituent), pyridyl group, pyridyloxy group, pyridyl lower alkoxy group, tetrahydroquinolyl group (on which an oxo group may be present), benzodioxolyl group, aryl lower alkoxy group (that may have on the aryl group a group selected from the group consisting of a halogen atom, lower alkyl group, lower alkoxy group and halogen substituted lower alkoxy group), aryl group (on which a group selected from the group consisting of a halogen atom, lower alkoxy group and hydroxy group may be present), aryloxy group (that may have on the aryl group a group selected from the group consisting of a cyano group, halogen atom, lower alkyl group, lower alkoxy group and halogen substituted lower alkyl group), aryl lower alkyl group (that may have on the aryl group a group selected from the group consisting of a halogen atom, lower alkyl group, lower alkoxy group and halogen substituted lower alkyl group) and aroyl group (that may have on the aryl group a group selected from the group consisting of a halogen atom and a lower alkoxy group) include

a piperidylcarbonyl group that may have 1 to 3 (preferably 1) substituents, on the piperidyl group, selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a hydroxy group;

a hydroxy lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms and having 1 to 3 hydroxy groups);

a lower alkanoyl group as illustrated above;

a carboxy lower alkyl group as illustrated above having a lower alkyl moiety as illustrated above;

a linear or branched alkyl group having 1 to 6 carbon atoms and substituted with a carbamoyl group having 1 to 2 lower alkyl groups as illustrated above (preferably linear or branched alkyl groups having 1 to 6 carbon atoms);

a carbamoyl group;

a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms);

a carboxy group;

a lower alkoxycarbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms),

an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group as illustrated above, a lower alkanoyl group as illustrated above, lower alkoxycarbonyl group as illustrated above and aroyl group as illustrated above may be present);

a piperidyl group (on which 1 to 3 groups (preferably 1) selected from the group consisting of a lower alkanoyl group as illustrated above, lower alkoxycarbonyl group as illustrated above and aroyl group as illustrated above may be present);

a piperazinyl group (on which 1 to 3 lower alkyl groups as illustrated above (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) may be present as a substituent(s));

a 1,4-dioxa-8-azasprio[4.5]decyl group;

a morpholinyl group;

a hexahydro-1,4-diazepinyl group (on which 1 to 3 lower alkyl groups as illustrated above (preferably linear or branched alkyl groups having 1 to 6 carbon atoms) may be present as a substituent(s));

a pyridyl group;

a pyridyloxy group;

a pyridyl lower alkoxy group having a lower alkoxy moiety as illustrated above;

a tetrahydroquinolyl group (on which 1 to 2 (preferably 1) oxo groups may be present);

a benzodioxolyl group (preferably benzo[1.3]dioxolyl group);

an aryl lower alkoxy group having an aryl moiety and lower alkoxy moiety as illustrated above (that may have on the aryl group 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a halogen atom as illustrated above, lower alkyl group as illustrated above, lower alkoxy group as illustrated above and halogen substituted lower alkoxy group as illustrated above);

an aryl group as illustrated above (that may have on the aryl group 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a halogen atom as illustrated above, lower alkoxy group as illustrated above and hydroxy group);

an aryloxy group having an aryl moiety as illustrated above (that may have on the aryl group 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a cyano group, halogen atom, lower alkyl group as illustrated above, lower alkoxy group as illustrated above and halogen substituted lower alkyl group as illustrated above);

an aryl lower alkyl group having an aryl moiety and lower alkyl moiety as illustrated above (that may have on the aryl group 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a halogen atom, lower alkyl group, lower alkoxy group and halogen substituted lower alkyl group); and

an aroyl group as illustrated above (that may have on the aryl group 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a halogen atom as illustrated above and a lower alkoxy group as illustrated above). Specific examples thereof include a (1-, 2-, 3-, or 4-)piperidylcarbonyl group, (1-, 2-, 3-, or 4-)ethyl-4-piperidylcarbonyl group, (2-, 3-, or 4-)methyl-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methyl-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methyl-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)methyl-4-piperidylcarbonyl group, (2-, 3-, or 4-)hydroxy-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)hydroxy-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)hydroxy-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)hydroxy-4-piperidylcarbonyl group, (2-, 3-, or 4-)hydroxymethyl-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)hydroxymethyl-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)hydroxymethyl-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)hydroxymethyl-4-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)(2-hydroxyethyl)-4-piperidylcarbonyl group, (2-, 3-, or 4-)(N-ethyl-carbamoylmethyl)-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(N-ethyl-carbamoylmethyl)-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(N-ethyl-carbamoylmethyl)-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)N-ethyl-carbamoylmethyl-4-piperidylcarbonyl group, (2-, 3-, or 4-)carbamoyl-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)carbamoyl-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)carbamoyl-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)carbamoyl-4-piperidylcarbonyl group, (2-, 3-, or 4-)carboxy-1-piperidylcarbonyl group, (2-, 3-, or 4-)carboxymethyl-1-piperidylcarbonyl group, (2-, 3-, or 4-)ethoxycarbonyl-1-piperidylcarbonyl group, (2-, 3-, or 4-)methoxy-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methoxy-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methoxy-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)methoxy-4-piperidylcarbonyl group, (2-, 3-, or 4-)methoxycarbonyl-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methoxycarbonyl-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methoxycarbonyl-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)methoxycarbonyl-4-piperidylcarbonyl group, (2-, 3-, or 4-)ethoxycarbonyl-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)ethoxycarbonyl-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)ethoxycarbonyl-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)ethoxycarbonyl-4-piperidylcarbonyl group, (2-, 3-, or 4-)acetylamino-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)acetylamino-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)acetylamino-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)acetylamino-4-piperidylcarbonyl group, (2-, 3-, or 4-)tert-butoxycarbonylamino-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)tert-butoxycarbonylamino-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)tert-butoxycarbonylamino-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)tert-butoxycarbonylamino-4-piperidylcarbonyl group, (2-, 3-, or 4-)butyrylamino-1-piperidylcarbonyl group, (2-, 3-, or 4-)benzoylamino-1-piperidylcarbonyl group, (2-, 3-, or 4-) (N-methyl-N-acetylamino)-1-piperidylcarbonyl group, (2-, 3-, or 4-)(N-methyl-N-butyrylamino)-1-piperidylcarbonyl group, (2-, 3-, or 4-)(N-methyl-N-tert-butoxycarbonylamino)-1-piperidylcarbonyl group, (2-, 3-, or 4-)(N-methyl-N-benzoylamino)-1-piperidylcarbonyl group, (2-, 3-, or 4-)[(1-, 2-, 3-, or 4-)piperidyl]-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[(1-, 2-, 3-, or 4-)piperidyl)-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[(1-, 2-, 3-, or 4-)piperidyl]-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-) [(1-, 2-, 3-, or 4-)piperidyl]-4-piperidylcarbonyl group, (2-, 3-, or 4-)[1-acetyl-(2-, 3-, or 4-)piperidyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [1-butyryl-(2-, 3-, or 4-)piperidyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [1-tert-butoxycarbonyl-(2-, 3-, or 4-)piperidyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-)[1-benzoyl-(2-, 3-, or 4-)piperidyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-)(1-piperazinyl)-1-piperidylcarbonyl group, (2-, 3-, or 4-)[1-(3,4-dimethylpiperazinyl)]-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[1-(3,4-dimethylpiperazinyl)]-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[1-(3,4-dimethylpiperazinyl)]-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-) [1-(3,4-dimethylpiperazinyl)]-4-piperidylcarbonyl group, (2-, 3-, or 4-)[1-(4-methylpiperazinyl)]-1-piperidylcarbonyl group, (1-, 3-, or 4-)[1-(4-methylpiperazinyl)]-2-piperidylcarbonyl group, (1-, 2-, or 4-) [1-(4-methylpiperazinyl)]-3-piperidylcarbonyl group, (1-, 2-, or 3-) [1-(4-methylpiperazinyl)]-4-piperidylcarbonyl group, (2-, 3-, or 4-)[(2-, 3-, or 4-)morpholinyl]-1-piperidylcarbonyl group, (1-, 3-, or 4-)[(2-, 3-, or 4-)morpholinyl]-2-piperidylcarbonyl group, (1-, 2-, 4-, 5-, or 6-)[(2-, 3-, or 4-)morpholinyl]-3-piperidylcarbonyl group, (1-, 2-, or 3-)[(2-, 3-, or 4-)morpholinyl]-4-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, 6-, or 7-)(4-methyl-hexahydro-1,4-diazepinyl)-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(4-methyl-hexahydro-1,4-diazepinyl)-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(4-methyl-hexahydro-1,4-diazepinyl)-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)(4-methyl-hexahydro-1,4-diazepinyl)-4-piperidylcarbonyl group, (2-, 3-, or 4-)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-piperidylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-piperidylcarbonyl group, (1-, 2-, 3-, or 4-)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-4-piperidylcarbonyl group, (2-, 3-, or 4-)[(2-, 4-, or 5-)benzo[1.3]dioxolyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [2-oxo-(1-, 3-, 4-, 5-, 6-, 7-, or 8-)-1,2,3,4-tetrahydroquinolyl]-1-piperidylcarbonyl group, 4-[2-oxo-(1-, 3-, 4-, 5-, 6-, 7-, or 8-)-1,2,3,4-tetrahydroquinolyl]-(2- or 3-methyl)-1-piperidylcarbonyl group, (2-, 3-, or 4-)[(2-, 3-, or 4-)pyridyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)pyridyloxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)pyridylmethoxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)fluorobenzyloxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)chlorobenzyloxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)bromobenzyloxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)methylbenzyloxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)trifluoromethoxybenzyloxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-)(3,4-dichlorobenzyloxy)-1-piperidylcarbonyl group, (2-, 3-, or 4-) (3,4-dimethoxybenzyloxy)-1-piperidylcarbonyl group, (2-, 3-, or 4-) (3-chloro-4-methoxybenzyloxy)-1-piperidylcarbonyl group, (2-, 3-, or 4-)[(2-, 3-, or 4-)fluorophenoxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)chlorophenoxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)cyanophenoxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-)[(2-, 3-, or 4-)methoxyphenoxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)methylphenoxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)trifluoromethoxyphenoxy]-1-piperidylcarbonyl group, (2-, 3-, or 4-)phenyl-1-piperidylcarbonyl group, 4-hydroxy-(2-, 3-, or 4-)phenyl-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)chlorophenyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)methoxyphenyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)hydroxyphenoxy]-1-piperidylcarbonyl group, 4-hydroxy-(2-, 3-, or 4-)phenyl-1-piperidylcarbonyl group, 4-ethoxycarbonyl-(2-, 3-, or 4-)phenyl-1-piperidylcarbonyl group, 4-hydroxy-(2-, 3-, or 4-)[(2-, 3-, or 4-)chlorophenyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-)benzyl-1-piperidylcarbonyl group, (2-, 3-, or 4-)[(2-, 3-, or 4-)chlorobenzyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)methylbenzyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)methoxybenzyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)trifluoromethoxybenzyl]-1-piperidylcarbonyl group, 4-hydroxy-(2-, 3-, or 4-)benzyl-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)chlorobenzoyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)methoxybenzoyl]-1-piperidylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)fluorobenzoyl]-1-piperidylcarbonyl group, and (2-, 3-, or 4-) [(2-, 3-, or 4-)trifluoromethoxybenzyl]-1-piperidylcarbonyl group.

Examples of the pyrrolidinylcarbonyl group that may have a substituent selected from the group consisting of a hydroxy lower alkyl group, carbamoyl group, hydroxy group, amino group (that may have a group selected from the group consisting of a lower alkyl group, lower alkanoyl group, and aroyl group thereon) morpholinyl lower alkyl group, pyrrolidinyl lower alkyl group, piperidyl lower alkyl group, piperazinyl lower alkyl group (that may have a lower alkyl group thereon as a substituent), amino lower alkyl group (that may have a lower alkyl group thereon as a substituent) and aryl oxy group (that may have on the aryl group a halogen substituted lower alkoxy group), aryloxy lower alkyl group (on the aryl group, a halogen substituted lower alkoxy group may be present) and a tetrahydroquinolyl group (on which an oxo group may be present) include a pyrrolidinylcarbonyl group that may have 1 to 3 (preferably 1) substituents, on the pyrrolidinyl group, which are selected from the group consisting of

a lower alkyl group as illustrated above having 1 to 3 hydroxy groups (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a carbamoyl group;

a hydroxy group;

an amino group (that may have 1 to 2 groups selected from the group consisting of a lower alkyl group as illustrated above, a lower alkanoyl group as illustrated above, and an aroyl group as illustrated above);

a morpholinyl lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms;

a pyrrolidinyl lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms;

a piperidyl lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms;

a piperazinyl lower alkyl group whose lower alkyl moiety is one as illustrated above preferably a linear or branched alkyl group having 1 to 6 carbon atoms (1 to 3 (preferably 1) lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present on the piperazinyl group, as a substituent(s)); an amino lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms (1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present on the amino group, as a substituent(s)), aryloxy group having an aryl moiety as illustrated above (which may have on the aryl group, 1 to 3 (preferably 1) halogen substituted lower alkoxy groups), aryloxy lower alkyl group having an aryl moiety and lower alkyl moiety as illustrated above (which may have on the aryl group, 1 to 3 (preferably 1) halogen substituted lower alkoxy groups) and a tetrahydroquinolyl group (on which a single oxo group may be present). Specific examples thereof include a (1-, 2-, or 3-)pyrrolidinylcarbonyl group, (2- or 3-)hydroxymethyl-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)hydroxymethyl-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)hydroxymethyl-3-pyrrolidinylcarbonyl group, (2- or 3-)carbamoyl-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)carbamoyl-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)carbamoyl-3-pyrrolidinylcarbonyl group, (2- or 3-)hydroxy-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)hydroxy-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)hydroxy-3-pyrrolidinylcarbonyl group, (2- or 3-)amino-1-pyrrolidinylcarbonyl group, (2- or 3-)acetamido-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)acetamido-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)acetamido-3-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)butyrylamino-3-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)(N-methyl-N-acetylamino)-3-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)(N-methyl-N-butyrylamino)-3-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)benzoylamino-3-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)(N-methyl-N-benzoylamino)-3-pyrrolidinylcarbonyl group, (2- or 3-)[(2-, 3-, or 4-)morpholinylmethyl]-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-) [(2-, 3-, or 4-)morpholinylmethyl]-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)[(2-, 3-, or 4-)morpholinylmethyl]-3-pyrrolidinylcarbonyl group, (2- or 3-)[(1-, 2-, or 3-)pyrrolidinylmethyl]-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)[(1-, 2-, or 3-)pyrrolidinylmethyl]]-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-) [(1-, 2-, or 3-)pyrrolidinylmethyl]]-3-pyrrolidinylcarbonyl group, (2- or 3-) [(1-, 2-, 3-, or 4-)piperidylmethyl]]-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-) [(1-, 2-, 3-, or 4-)piperidylmethyl]]-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)[(1-, 2-, 3-, or 4-)piperidylmethyl)]-3-pyrrolidinylcarbonyl group, (2- or 3-)(4-methyl-1-piperazinylmethyl)-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)(4-methyl-1-piperazinylmethyl)-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)(4-methyl-1-piperazinylmethyl)-3-pyrrolidinylcarbonyl group, (2- or 3-)N,N-dimethylaminomethyl-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)N,N-dimethylaminomethyl-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)N,N-dimethylaminomethyl-3-pyrrolidinylcarbonyl group, (2- or 3-)N,N-diethylaminomethyl-1-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)N,N-diethylaminomethyl-2-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)N,N-diethylaminomethyl-3-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)(4-trifluoromethoxyphenoxymethyl)-3-pyrrolidinylcarbonyl group, (1-, 2-, 3-, 4-, or 5-)(4-trifluoromethoxyphenoxy)-3-pyrrolidinylcarbonyl group, and (1-, 3-, 4-, 5-, 6-, 7-, or 8-)(2-oxy-1,2,3,4-tetrahydroquinolyl)-3-pyrrolidinylcarbonyl group.

Examples of a piperazinylcarbonyl group that may have a substituent selected from the group consisting of a lower alkyl group, cyclo C3-C8 alkyl group, lower alkanoyl group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyl group, amino lower alkyl group (a lower alkyl group may be present on the amino group, as a substituent), piperidyl lower alkyl group (a lower alkyl group may be present on the piperidyl group, as a substituent), morpholinyl lower alkyl group, pyrrolidinyl lower alkyl group, 1,3-dioxolanyl lower alkyl group, tetrahydrofuryl lower alkyl group, pyridyl lower alkyl group (a phenyl group may be present on the lower alkyl group as a substituent), imidazolyl lower alkyl group, furyl lower alkyl group, pyrrolidinyl carbonyl lower alkyl group, piperidyl group that may have a lower alkyl group as a substituent, pyridyl group (a substituent selected from the group consisting of a lower alkyl group, cyano group, and halogen substituted lower alkyl group may be present on the pyridyl group, as a substituent), thieno[2,3-c]pyridyl group aryl group (on which a group selected from the group consisting of a halogen atom and a lower alkyl group may be present), aroyl group, furyl lower alkyl group, aryl lower alkoxycarbonyl group and oxo group, include a piperazinylcarbonyl group that may have 1 to 3 (preferably 1) substituents, on the piperazinyl group, which are selected from the group consisting of

a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms);

a cyclo C3-C8 alkyl group as illustrated above;

a lower alkanoyl group as illustrated above (preferably a linear or branched alkanoyl group having 1 to 6 carbon atoms);

a hydroxy lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms with 1 to 3 hydroxy groups);

a lower alkoxy lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms and 1 to 3 lower alkoxy groups as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms));

a lower alkoxycarbonyl group as illustrated above (preferably a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms);

an amino lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms (1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present on the amino group, as substituent(s)); a piperidyl lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms (1 to 3 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present on the piperidyl group as a substituent(s)); a morpholinyl lower alkyl group whose alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms; a pyrrolidinyl lower alkyl group whose alkyl moiety is one as illustrated above preferably a linear or branched alkyl group having 1 to 6 carbon atoms; a 1,3 dioxolanyl lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms; a tetrahydrofuryl lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms; a pyridyl lower alkyl group whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms (1 to 3 phenyl groups may be present on the alkyl group, as a substituent(s)); an imidazolyl lower alkyl group, whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms; a furyl lower alkyl group, whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms; a pyrrolidinyl carbonyl lower alkyl group, whose lower alkyl moiety is one as illustrated above, preferably a linear or branched alkyl group having 1 to 6 carbon atoms; a piperidyl group that may have 1 to 3 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms); a pyridyl group (1 to 3 groups (preferably 1) selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms), cyano group, and halogen substituted lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 7 halogen atoms) may be present on the pyridyl group); a tieno[2,3-c]pyridyl group; aryl group as illustrated above (which may have on the aryl group 1 to 3 (preferably 1) groups selected from the group consisting of a halogen atom and a lower alkyl group), aroyl group as illustrated above, furyl lower alkyl group having a lower alkyl moiety as illustrated above, aryl lower alkoxy carbonyl group having an aryl moiety and lower alkoxy carbonyl moiety as illustrated above and oxo group. Specific examples thereof include a (t- or 2-)piperazinylcarbonyl group, (2-, 3-, or 4-)methyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)ethyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)ethyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)n-propyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)n-propyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)n-butyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)n-butyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-) [(1-ethyl-n-propyl)]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[(1-ethyl-n-propyl)]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)isopropyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)isopropyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)tert-butyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)tert-butyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)n-hexyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)n-hexyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)cyclopentyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)cyclopentyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)cycloheptyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)cycloheptyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)acetyl-1-piperazinylcarbonyl group, (2-, 3-, or 4-)butyryl-1-piperazinyl carbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)acetyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(2-hydroxyethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(2-hydroxyethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(2-methoxyethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(2-methoxyethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(3-methoxypropyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(3-methoxypropyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(4-methoxybutyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(4-methoxybutyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)ethoxycarbonyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)ethoxycarbonyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)tert-butoxycarbonyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)tert-butoxycarbonyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)methoxycarbonyl-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)methoxycarbonyl-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[3-(N,N-dimethylamino)propyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[3-(N,N-dimethylamino)propyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[2-(N,N-dimethylamino)ethyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(2-(N,N-dimethylamino)ethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(2-(1-piperidyl)ethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(2-(1-piperidyl)ethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[(1-methyl-3-piperidyl)methyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[(1-methyl-3-piperidyl)methyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-) [(1-methyl-4-piperidyl)methyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[(1-methyl-4-piperidyl)methyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[2-(4-morpholinyl)ethyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[2-(4-morpholinyl)ethyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[2-(1-pyrrolidinyl)ethyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[2-(1-pyrrolidinyl)ethyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[2-(1,3-dioxolanyl)methyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[2-(1,3-dioxolanyl)methyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-){2-[2-(1,3-dioxolanyl)]ethyl}-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-){2-[2-(1,3-dioxolanyl)]ethyl}-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(2-tetrahydrofurylmethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(2-tetrahydrofurylmethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(2-pyridylmethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(2-pyridylmethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(3-pyridylmethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(3-pyridylmethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(4-pyridylmethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(4-pyridylmethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-) [2-(4-pyridyl)ethyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[2-(4-pyridyl)ethyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-) [2-(2-pyridyl)ethyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[2-(2-pyridyl)ethyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[2-phenyl-2-(4-pyridyl)ethyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[2-phenyl-2-(4-pyridyl)ethyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[2-(1-imidazolyl)ethyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[2-(1-imidazolyl)ethyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(3-furylmethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(3-furylmethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(1-pyrrolidinylcarbonylmethyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(1-pyrrolidinylcarbonylmethyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(1-methyl-4-piperidyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(1-methyl-4-piperidyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[(2-, 3-, or 4-)pyridyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(2-, 3-, or 4-pyridyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(3-cyano-2-pyridyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(3-cyano-2-pyridyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-){4-methyl-2-pyridyl}-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(4-methyl-2-pyridyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(3-methyl-2-pyridyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(3-methyl-2-pyridyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)(3-trifluoromethyl-2-pyridyl)-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)(3-trifluoromethyl-2-pyridyl)-2-piperazinylcarbonyl group, (2-, 3-, or 4-)[(2-, 3-, 4-, 5-, or 6-)thieno[2,3-c]pyridyl]-1-piperazinylcarbonyl group, (1-, 2-, 3-, 4-, 5-, or 6-)[(2-, 3-, 4-, 5-, or 6-)thieno[2,3-c]pyridyl]-2-piperazinylcarbonyl group, (2-, 3-, or 4-)phenyl-1-piperazinylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)chlorophenyl]-1-piperazinylcarbonyl group, (2-, 3-, or 4-) [(2-, 3-, or 4-)methylphenyl]-1-piperazinylcarbonyl group, 3-oxo-(2- or 4-)phenyl-1-piperazinylcarbonyl group, (2-, 3-, or 4-)benzolyl-1-piperazinylcarbonyl group, (2-, 3-, or 4-) [(2- or 3-)furylcarbonyl]-1-piperazinylcarbonyl group, and (2-, 3-, or 4-)benzyloxycarbonyl-1-piperazinylcarbonyl group.

Example of a hexahydroazepinylcarbonyl group include a (1-, 2-, 3- or 4-)hexahydroazepinylcarbonyl group.

Example of a hexahydro-1,4-diazepinylcarbonyl group that may have a substituent selected from the group consisting of a lower alkyl group and a pyridyl group include a hexahydro-1,4-diazepinylcarbonyl group that may have 1 to 3, preferably 1, substituents selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) and a pyridyl group. Specific examples thereof include a (hexahydro-1,4-diazepin-(1-, 2-, 5- or 6-)yl)carbonyl group, (4-methyl-hexahydro-1,4-diazepin-1-yl)carbonyl group, and (4-(4-pyridyl)-methyl-hexahydro-1,4-diazepin-1-yl)carbonyl group.

Example of a dihydropyrrolylcarbonyl group include a 2,3-dihydropyrrolylcarbonyl group and a 2,5-dihydropyrrolylcarbonyl group.

Examples of the dihydropyrrolylcarbonyl group that may have a lower alkyl group include a dihydropyrrolylcarbonyl group as illustrated above that may have 1 to 4, preferably 1 to 2 lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a (1-, 2- or 3-)(2,5-dihydropyrrolylcarbonyl) group, 2,5-dimethyl-1-(2,5-dihydropyrrolylcarbonyl) group, and 2,5-dimethyl-1-(2,3-dihydropyrrolylcarbonyl) group.

Examples of the thiomorpholinylcarbonyl group include a (2-, 3- or 4-)thiomorpholinylcarbonyl group.

Examples of the morpholinylcarbonyl group that may have a group selected from the group consisting of a lower alkyl group, and piperidyl lower alkyl group, and aryl group include a morpholinylcarbonyl group that may have 1 to 5 groups, more preferably 1 to 2 groups selected from the group consisting of a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) (on which 1 to 3 (preferably 1) piperidyl groups may be present as substituent(s)) an aryl group as described above. Specific examples thereof include a (2-, 3- or 4-)morpholinylcarbonyl group, 2,6-dimethyl-4-morpholinylcarbonyl group, 2-(1-piperidylmethyl)-4-morpholinylcarbonyl group, and 2-phenyl-4-morpholinylcarbonyl group.

Examples of the thiazolidinylcarbonyl group include a (2-, 3-, 4- or 5-) thiazolidinylcarbonyl group.

Examples of the thiazolidinylcarbonyl group that may have an aryl group that may have a group selected from the group consisting of a lower alkoxy group and a cyano group include a thiazolidinylcarbonyl group that may have 1 to 3 (preferably 1) aryl groups that may have 1 to 3 (preferably 1) groups selected from the group consisting of a lower alkoxy group and a cyano group as illustrated above. Specific examples thereof include a (2-, 3-, 4- or 5-)thiazolidinylcarbonyl group, (2-, 4- or 5-) [(2-, 3- or 4-)methoxyphenyl]-3-thiazolidinylcarbonyl group and (2-, 4- or 5-) [(2-, 3- or 4-)cyanophenyl]-3-thiazolidinylcarbonyl group.

Examples of the azabicyclo[3.2.2]nonylcarbonyl group include a 1-azabicyclo[3.2.2]non-(2-, 3-, 5-, or 6-)ylcarbonyl group, 2-azabicyclo[3.2.2]non-(1-, 2-, 3-, 4-, 5-, 6- or 7-)ylcarbonyl group, 3-azabicyclo[3.2.2]non-(1-, 2-, 3-, or 6-)ylcarbonyl group, and 6-azabicyclo[3.2.2]non-(1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)ylcarbonyl group.

Examples of the azabicyclo[3.2.1]octylcarbonyl group that may have a halogen substituted or unsubstituted aryloxy group include an azabicyclo[3.2.1]octylcarbonyl group that may have 1 to 2 (preferably 1) halogen substituted aryl groups as illustrated above (preferably an aryl group that may be substituted with 1 to 3, preferably 1 halogen atom), or an azabicyclo[3.2.1]octylcarbonyl group that may have 1 to 2 (preferably 1) unsubstituted aryl groups as illustrated above. Specific examples thereof include a 1-azabicyclo[3.2.1]oct-(2-, 3-, 4-, 5-, 6-, 7-, or 8-)ylcarbonyl group, 2-azabicyclo[3.2.1]oct-(1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-) ylcarbonyl group, 3-azabicyclo[3.2.1]oct-(1-, 2-, 3-, 6-, or 8-)ylcarbonyl group, 6-azabicyclo[3.2.1]oct-(1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-)ylcarbonyl group, 8-azabicyclo[3.2.1]oct-(1-, 2-, 3-, 6-, or 8-)ylcarbonyl group, 3-(phenyloxy)-1-azabicyclo[3.2.1]oct-2-ylcarbonyl group, 3-(2-biphenyloxy)-1-azabicyclo[3.2.1]oct-3-ylcarbonyl group, 3-(1-naphthyloxy)-1-azabicyclo[3.2.1]oct-4-ylcarbonyl group, 3-(3-methylphenyloxy)-1-azabicyclo[3.2.1]oct-5-ylcarbonyl group, 3-(4-ethylphenyloxy)-1-azabicyclo[3.2.1]oct-6-ylcarbonyl group, 3-(2-n-propylphenyloxy)-1-azabicyclo[3.2.1]oct-7-ylcarbonyl group, 3-(3-n-butylphenyloxy)-1-azabicyclo[3.2.1]oct-8-ylcarbonyl group, 3-(4-n-pentylphenyloxy)-2-azabicyclo[3.2.1]oct-1-ylcarbonyl group, 3-(2-n-hexylphenyloxy)-2-azabicyclo[3.2.1]oct-2-ylcarbonyl group, 3-(3-isobutylphenyloxy)-2-azabicyclo[3.2.1]oct-3-ylcarbonyl group, 3-(4-tert-butylphenyloxy)-2-azabicyclo[3.2.1]oct-4-ylcarbonyl group, 3-(2-chlorophenyloxy)-2-azabicyclo[3.2.1]oct-5-ylcarbonyl group, 3-(3-fluorophenyloxy)-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl group, 3-(3-bromophenyloxy)-2-azabicyclo[3.2.1]oct-6-ylcarbonyl group, 3-(2-aminophenyloxy)-2-azabicyclo[3.2.1]oct-7-ylcarbonyl group, 3-(2,3-dimethylphenyloxy)-2-azabicyclo[3.2.1]oct-8-ylcarbonyl group, 3-(3,4,5-trimethylphenyloxy)-8-azabicyclo[3.2.1]oct-1-ylcarbonyl group, and 3-(2,3-diaminophenyloxy)-8-azabicyclo[3.2.1]oct-2-ylcarbonyl group.

Examples of the indolinylcarbonyl group include a (1-, 2-, 3-, 4-, 5-, 6-, or 7-)indolinylcarbonyl group.

Examples of the tetrahydropyrido[3.4-b]indolylcarbonyl group include a (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)(2-, 3-, 4-, 9-tetrahydropyrido[3.4-b]indolylcarbonyl) group.

Examples of the piperazinyl lower alkyl group that may have a lower alkyl group on the piperazinyl group include a piperazinyl lower alkyl group whose lower alkyl moiety is a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) and 1 to 7, preferably 1 to 5, more preferably 1, lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) may be present on the piperazinyl group. Specific examples thereof include a (1- or 2-)piperazinylmethyl group, 2-[(1- or 2-)piperazinyl]ethyl group, 1-[(1- or 2-)piperazinyl]ethyl group, 3-[(1- or 2-)piperazinyl]propyl group, 4-[(1- or 2-)piperazinyl]butyl group, 5-[(1- or 2-)piperazinyl]pentyl group, 6-[(1- or 2-)piperazinyl]hexyl group, 1,1-dimethyl-2-[(1- or 2-)piperazinyl]ethyl group, 2-methyl-3-[(1- or 2-)piperazinyl]propyl group, 4-methyl-1-piperazinylmethyl group, 2-(4-methyl-2-piperazinyl)ethyl group, 3-(2-ethyl-1-piperazinyl)propyl group, 4-(3-n-propyl-1-piperazinyl)butyl group, 5-(4-n-butyl-1-piperazinyl)pentyl group, 6-(1-n-pentyl-2-piperazinyl)hexyl group, 2-n-hexyl-2-piperazinylmethyl group, 2-(3-isobutyl-2-piperazinyl)ethyl group, and 3-(4-tert-butyl-2-piperazinyl)propyl group.

Examples of the morpholinylcarbonyl lower alkyl group include a morpholinylcarbonyl lower alkyl group whose lower alkyl moiety is a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms). Specific examples thereof include a 2-morpholinylcarbonylmethyl group, 3-morpholinylcarbonylmethyl group, 4-morpholinylcarbonylmethyl group, 2-(2-morpholinylcarbonyl)ethyl group, 2-(3-morpholinylcarbonyl)ethyl group, 2-(4-morpholinylcarbonyl)ethyl group, 1-(2-morpholinylcarbonyl)ethyl group, 1-(3-morpholinylcarbonyl)ethyl group, 1-(4-morpholinylcarbonyl)ethyl group, 3-(2-morpholinylcarbonyl)propyl group, 3-(3-morpholinylcarbonyl)propyl group, 3-(4-morpholinylcarbonyl)propyl group, 4-(2-morpholinylcarbonyl)butyl group, 4-(3-morpholinylcarbonyl)butyl group, 4-(4-morpholinylcarbonyl)butyl group, 5-(2-morpholinylcarbonyl)pentyl group, 5-(3-morpholinylcarbonyl)pentyl group, 5-(4-morpholinylcarbonyl)pentyl group, 6-(2-morpholinylcarbonyl)hexyl group, 6-(3-morpholinylcarbonyl)hexyl group, 6-(4-morpholinylcarbonyl)hexyl group, 3-methyl-3-(2-morpholinylcarbonyl)propyl group, 3-methyl-3-(3-morpholinylcarbonyl)propyl group, 3-methyl-3-(4-morpholinylcarbonyl)propyl group, 1,1-dimethyl-2-(2-morpholinylcarbonyl)ethyl group, 1,1-dimethyl-2-(3-morpholinylcarbonyl)ethyl group, and 1,1-dimethyl-2-(4-morpholinylcarbonyl)ethyl group.

Examples of the piperazinylcarbonyl lower alkyl group that may have a lower alkyl group on the piperazinyl group include a piperazinylcarbonyl lower alkyl group whose lower alkyl moiety is a lower alkyl group as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) and which may have 1 to 7, preferably 1 to 5, more preferably 1, lower alkyl groups as illustrated above (preferably a linear or branched alkyl group having 1 to 6 carbon atoms) on the piperazinyl group. Specific examples thereof include a (1- or 2-)piperazinylcarbonylmethyl group, 2-[(1- or 2-)piperazinylcarbonyl]ethyl group, 1-[(1- or 2-)piperazinylcarbonyl]ethyl group, 3-[(1- or 2-)piperazinylcarbonyl]propyl group, 4-[(1- or 2-)piperazinylcarbonyl]butyl group, 5-[(1- or 2-)piperazinylcarbonyl]pentyl group, 6-[(1- or 2-)piperazinylcarbonyl]hexyl group, 1,1-dimethyl-2-[1- or 2-)piperazinylcarbonyl]ethyl group, 2-methyl-3-[(1- or 2-)piperazinylcarbonyl]propyl group, 4-methyl-1-piperazinylcarbonylmethyl group, 2-(4-methyl-2-piperazinylcarbonyl)ethyl group, 3-(2-ethyl-1-piperazinylcarbonyl)propyl group, 4-(3-n-propyl-1-piperazinylcarbonyl)butyl group, 5-(4-n-butyl-1-piperazinylcarbonyl)pentyl group, 6-(1-n-pentyl-2-piperazinylcarbonyl)hexyl group, 2-n-hexyl-2-piperazinylcarbonylmethyl group, 2-(3-isobutyl-2-piperazinylcarbonyl)ethyl group, and 3-(4-tert-butyl-2-piperazinylcarbonyl)propyl group.

Examples of the amino lower alkoxy group (on the amino group, a lower alkyl group may be present) include a lower alkoxy group as illustrated above (preferably a linear or branched alkoxy group having 1 to 6 carbon atoms) having 1 to 5 (preferably 1) amino groups that may have 1 to 2 lower alkyl groups as illustrated above. Specific examples thereof include an amino methoxy group, 2-amino ethoxy group, 1-aminoethoxy group, 3-aminopropoxy group, 4-aminobutoxy group, 5-aminopentoxy group, 6-aminohexyloxy group, 1,1-dimethyl-2-aminoethoxy group, N,N-dimethylaminomethoxy group, N-methyl-N-ethylaminomethoxy group, N-methylaminomethoxy group, 2-(N-methylamino)ethoxy group, 2-(N,N-dimethylamino)ethoxy group, 2-(N,N-diethylamino)ethoxy group, 2-(N,N-diisopropylamino)ethoxy group and 3-(N,N-dimethylamino)propoxy group.

Examples of the lower alkoxy lower alkoxy group include a lower alkoxy lower alkoxy group having a lower alkoxy moiety as illustrated above. Specific examples thereof include a methoxymethoxy group, 2-methoxyethoxy group, 1-ethoxyethoxy group, 2-ethoxyethoxy group, 2-isobutoxyethoxy group, 2,2-dimethtoxyethoxy group and 2-methoxy-1-methylethoxy group.

Examples of the piperazinyl group that may have a group selected from the group consisting of an oxo group, lower alkyl group, lower alkanoyl group and lower alkoxy carbonyl group include a piperazinyl group that may have a group 1 to 3 (1 to 2) groups selected from the group consisting of an oxo group, lower alkyl group as illustrated above, lower alkanoyl group as illustrated above and lower alkoxy carbonyl group as illustrated above. Specific examples thereof include a (1- or 2-)piperazinyl group, (2-, 3- or 4-)methyl-1-piperazinyl group, (1-, 2-, 3-, 4-, 5- or 6-)methyl-2-piperazinyl group, (2-, 3- or 4-)ethyl-1-piperazinyl group, (1-, 2-, 3-, 4-, 5- or 6-)ethyl-2-piperazinyl group, (2-, 3- or 4-)n-propyl-1-piperazinyl group, (1-, 2-, 3-, 4-, 5- or 6-)n-propyl-2-piperazinyl group, (2-, 3- or 4-)formyl-1-piperazinyl group, (2-, 3- or 4-)acetyl-1-piperazinyl group, (2-, 3- or 4-)propionyl-1-piperazinyl group, (1-, 2-, 3-, 4-, 5- or 6-)propionyl-2-piperazinyl group, (2-, 3- or 4-)butyryl-1-piperazinyl group, (1-, 2-, 3-, 4-, 5- or 6-)butyryl-2-piperazinyl group, (2-, 3- or 4-)methoxycarbonyl-1-piperazinyl group, (2-, 3- or 4-)ethoxycarbonyl-1-piperazinyl group, (2-, 3- or 4-)tert-butoxycarbonyl-1-piperazinyl group, (2- or 3-)oxo-1-piperazinyl group, 2-oxo-(3-, 4-, 5- or 6-)acetyl-1-piperazinyl group, 2-oxo-(3-, 4-, 5- or 6-)butyryl-1-piperazinyl group, 2-oxo-(3-, 4-, 5- or 6-)methoxycarbonyl-1-piperazinyl group and 2-oxo-(3-, 4-, 5- or 6-)methoxycarbonyl-1-piperazinyl group.

Examples of the 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have a group selected from the group consisting of an oxo group and an aryl group include a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have 1 to 3 (1 to 2) groups selected from the group consisting of an oxo group and an aryl group as illustrated above. Specific examples thereof include a 1,3,8-triazaspiro[4.5]decanyl-(1, 2, 3, 4 or 8-)ylcarbonyl group, 1-phenyl-1,3,8-triazaspiro[4.5]decanyl-8-ylcarbonyl group and 1-phenyl-4-oxo-1,3,8-triazaspiro[4.5]decanyl-8-ylcarbonyl group.

Examples of the tetrahydropyridyl group include a (1-, 2-, 3-, 4-, 5- or 6-)-1,2,3,4-tetrahydropyridyl group and (1-, 2-, 3-, 4-, 5- or 6-)-1,2,3,6-tetrahydropyridyl group.

Examples of the tetrahydropyridylcarbonyl group that may have a pyridyl group include a tetrahydropyridylcarbonyl group as illustrated above that may have 1 to 3 (preferably 1) pyridyl groups. Specific examples thereof include a (2-, 3- or -4)pyridyl-1,2,3,6-tetrahydropyridyl-1-ylcarbonyl group.

Examples of the imidazolidinylcarbonyl group that may have a thioxo group include an imidazolidinylcarbonyl group that may have 1 to 2 (preferably 1) thioxo groups. Specific examples thereof include a 2-thioxo-1-imidazolidinylcarbonyl group.

Examples of the tetrahydronaphthyl group include a (1- or 2-)-1,2,3,4-tetrahydronaphthyl group.

Examples of the saturated or unsaturated heteromonocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom include a heteromonocyclic groups represented by (1) to (9) below.

(1) a saturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 4 (preferably 1 to 2) nitrogen atoms (for example, pyrrolidinyl group, imidazolidinyl group, piperidyl group, hexahydropyrimidinyl group, piperazinyl group, azepanyl group and azocanyl group);

(2) an unsaturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 4 (preferably 1 to 3) nitrogen atoms, for example, a pyrrolyl group, dihydropyrrolyl group such as 1H-2,5-dihydropyrolyl group, imidazolyl group (such as 1H-imidazolyl group), dihydroimidazolyl group (such as 1H-2,3-dihydroimidazolyl group), triazolyl group (such as 4H-1,2,4-trizaolyl group, 1H-1,2,3-trizaolyl group, and 2H-1,2,3-trizaolyl group), dihydrotriazolyl group (such as 1H-4,5-dihydro-1,2,4-triazolyl group), pyrazolyl group, pyridyl group, dihydropyridyl group (such as 1,2-dihydropyridyl group), pyrimidinyl group, dihydropyrimidinyl group (such as 1,6-dihydropyrimidinyl group), pyrazinyl group, dihydropyrazinyl group (such as 1,2-dihydropyrazinyl), pyridazinyl group, and tetrazolyl group (such as 1H-tetrazolyl group and 2H-tetrazolyl group);

(3) an unsaturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms, for example, an oxazolyl group, isoxazolyl group, oxadiazolyl group (such as 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group and 1,2,5-oxadiazolyl group) and a saturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 2 (preferably 1) oxygen atoms and 1 to 3 (preferably 1 to 2) nitrogen atoms, for example an oxazolidinyl group, isoxazolidinyl group and morpholinyl group;

(4) an unsaturated 3 to 8 (preferably 5) membered heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, a thiazolyl group, dihydrothiazolyl group (such as 2,3-dihydrothiazolyl group), isothiazolyl group, thiadiazolyl group (such as, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, and 1,2,5-thiadiazolyl group) and dihydrothiazinyl group.

(5) a saturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, a thiazolidinyl group;

(6) a saturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 2 oxygen atom, for example, a tetrahydrofuryl group and a tetrahydropyranyl group;

(7) an unsaturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 2 oxygen atoms, for example, a pyranyl group (such as 2H-pyranyl group);

(8) a saturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 2 sulfur atoms, for example, a tetrahydrothiofuryl group and a tetrahydrothiopyranyl group; and

(9) an unsaturated 3 to 8 (preferably 5 to 6) membered heteromonocyclic group having 1 to 2 sulfur atoms, for example, a thienyl group and a thiopyranyl group (such as 2H-thiopyranyl).

Of them, mention may be preferably made of a saturated or unsaturated heteromonocyclic group having a 1 to 2 hetero atoms selected from a nitrogen atom, oxygen atom and sulfur atom and selected from the group consisting of a pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, isoxazolyl group, thiazolyl group, pyranyl group and thienyl group; and further preferably made of a saturated or unsaturated heteromonocyclic group having a 1 to 2 nitrogen atoms and selected from the group a pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group and thiazolyl group.

Examples of the tetrahydroquinoxalinyl group include a (1-, 2-, 5- or 6-)-1,2,3,4-tetrahydroquinoxalinyl group and (1-, 2-, 5- or 6-)-5,6,7,8-tetrahydroquinoxalinyl group.

Examples of the tetrahydroquinazolinyl group include a (1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-)-1,2,3,4-tetrahydroquinazolinyl group and (1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-)-5,6,7,8-tetrahydroquinazolinyl group.

Examples of the dihydroquinazolinyl group include a (1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-)-3,4-dihydroquinazolinyl group and (1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-)-1,2-dihydroquinazolinyl group.

Examples of the dihydrobenzimidazolyl group include a (1-, 2-, 4- or 5-)-2,3-dihydro-1H-benzimidazolyl group.

Examples of the tetrahydrobenzazepinyl group include a (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)-2,3,4,5-tetrahydro-1H-benzo[b]azepinyl group and (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)-2,3,4,5-tetrahydro-1H-benzo[c]azepinyl group.

Examples of the tetrahydrobenzodiazepinyl group include a (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)-2,3,4,5-tetrahydro-1H-benzo[b][1.4]diazepinyl group and (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)-2,3,4,5-tetrahydro-1H-benzo[e][1.4]diazepinyl group.

Examples of the hexahydrobenzazocinyl group include a (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-)-1,2,3,4,5,6-tetrahydrobenzo[b]azocinyl group and (1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-)-1,2,3,4,5,6-hexahydrobenzo[c]azocinyl group.

Examples of the dihydrobenzoxazinyl group include a (2-, 3-, 4-, 5-, 6-, 7- or 8-)-3,4-dihydro-2H-benzo[b][1.4]oxazinyl group and (1-, 2-, 4-, 5-, 6-, 7- or 8-)-2,4-dihydro-1H-benzo[d][1.3]oxazinyl group.

Examples of the dihydrobenzoxazolyl group include a (2-, 3-, 4-, 5-, 6- or 7-)-2,3-dihydrobenzoxazolyl group.

Examples of the benzisoxazolyl group include a (3-, 4-, 5-, 6- or 7-)-benzo[d]-isoxazolyl group and (3-, 4-, 5-, 6- or 7-)-benzo[c]-isoxazolyl group.

Examples of the benzoxadiazolyl group include a (4- or 5-)-benzo[c][1.2.5]oxadiazolyl group.

Examples of the tetrahydrobenzoxazepinyl group include a (2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)-2,3,4,5-tetrahydrobenzo[b][1.4]oxazepinyl group, (1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)-1,3,4,5-tetrahydrobenzo[e][1.3]oxazepinyl group and (2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-)-2,3,4,5-tetrahydrobenzo[f][1.4]oxazepinyl group.

Examples of the dihydrobenzothiazinyl group include a (2-, 3-, 4-, 5-, 6-, 7- or 8-)-3,4-dihydro-2H-benzo[b][1.4]thiazinyl group and (2-, 3-, 4-, 5-, 6-, 7- or 8-)-3,4-dihydro-2H-benzo[e][1.3]thiazinyl group.

Examples of the benzoxathiolyl group include a (2-, 4-, 5-, 6- or 7-)-benzo[d][1.3]oxathiolyl group, (3-, 4-, 5-, 6- or 7-)-3H-benzo[c][1.2]oxathiolyl group and (3-, 4-, 5-, 6- or 7-)-3H-benzo[d][1.2]oxathiolyl group.

Examples of the dihydrobenzofuryl group include a (2-, 3-, 4-, 5-, 6- or 7-)-2,3-dihydrobenzofuryl group.

A heterocyclic compound (hereinafter referred to as a compound (1)) represented by the general formula (1) can be produced by various kinds of methods, for example, a method shown in the following reaction formula-1 or reaction formula 2.

wherein R¹, R² and A are the same as defined above; and X¹ is a halogen atom or a group mediating the same substitution reaction as in a halogen atom.

Examples of the group mediating the same substitution reaction as in a halogen atom include a lower alkanesulfonyloxy group, arylsulfonyloxy group, and aralkylsulfonyloxy group.

A halogen atom represented by X¹ in the general formula (2) is a fluorine atom, chlorine atom, bromine atom and iodine atom.

Specific examples of the lower alkanesulfonyloxy group represented by X¹ include a linear or branched alkanesulfonyloxy group having 1 to 6 carbon atoms such as a methanesulfonyloxy group ethanesulfonyloxy group, isopropanesulfonyloxy group, n-propanesulfonyloxy group, n-butanesulfonyloxy group, tert-butanesulfonyloxy group, n-pentanesulfonyloxy group, and n-hexanesulfonyloxy group.

Specific examples of the arylsulfonyloxy group represented by X¹ include a phenylsulfonyloxy group and naphthylsulfonyloxy group that may have 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, a nitro group, and a halogen atom, on the phenyl ring. Specific examples of the phenylsulfonyloxy group that may have a substituent include a phenylsulfonyloxy group, 4-methylphenylsulfonyloxy group, 2-methylphenylsulfonyloxy group, 4-nitrophenylsulfonyloxy group, 4-methoxyphenylsulfonyloxy group, 2-nitrophenylsulfonyloxy group, and 3-chlorophenylsulfonyloxy group. Specific examples of the naphthylsulfonyloxy group include α-naphthylsulfonyloxy group and β-naphthylsulfonyloxy group.

Examples of the aralkylsulfonyloxy group represented by X¹ include a linear or branched alkylsulfonyloxy group having 1 to 6 carbon atoms and substituted with a phenyl group; and

a linear or branched alkylsulfonyloxy group having 1 to 6 carbon atoms and substituted with a naphthyl group; both of which may have 1 to 3 substituents selected from the group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, a nitro group and a halogen atom, on the phenyl ring. Specific examples of the alkylsulfonyloxy group substituted with a phenyl group as mentioned above include a benzylsulfonyloxy group, 2-phenylethylsulfonyloxy group, 4-phenylbutylsulfonyloxy group, 2-methylbenzylsulfonyloxy group, 4-methoxybenzylsulfonyloxy group, 4-nitrobenzylsulfonyloxy group, and 3-chlorobenzylsulfonyloxy group. Specific examples of the alkylsulfonyloxy group substituted with a naphthyl group include an α-naphthylmethylsulfonyloxy group and β-naphthylmethylsulfonyloxy group.

The compound (1) can be produced by reacting a compound (hereinafter referred to as a compound (2)) represented by the general formula (2) and a compound (hereinafter referred to as a compound (3)) represented by the general formula (3).

This reaction is generally performed in a conventional solvent that may not negatively affect the reaction, such as water; an alcohol based solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; a ketone based solvent such as acetone and methylethyl ketone; an ether based solvent such as tetrahydrofuran, dioxane, diethyl ether, and diglyme; an ester based solvent such as methyl acetate and ethyl acetate; a non-proton polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethylsulfoxide; a halogenated hydrocarbon based solvent such as methylene chloride and ethylene chloride; or other organic solvents. Furthermore, the reaction can be performed in a solution mixture of these conventional solvents. The reaction is generally performed in the presence of an inorganic base such as an alkali metal (e.g., sodium and potassium), an alkaline metal hydrogen carbonate (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate), alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkali metal carbonate (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), alkali metal lower alkoxide (e.g., sodium methoxide and sodium ethoxide), and a hydride (e.g., sodium hydride and potassium hydride); or in the presence of an organic base such as a trialkylamine (e.g., trimethylamine, triethylamine, N-ethyl diisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undecene-7 (DBU). When these bases take liquid form, they can be used as solvents.

These basic compounds may be used alone or in a mixture of two types or more.

A basic compound may be used in a molar amount, which is generally 0.5 to 10 times, preferably 0.5 to 6 times as large as that of the compound (2).

The reaction mentioned above may be performed, if necessary, with the addition of an alkaline metal iodide serving as an accelerator, such as potassium iodide and sodium iodide.

The ratio of a compound (2) to a compound (3) used in the reaction formula-1 may be at least about 0.5 times mole, preferably about 0.5-5 times by mole.

The reaction temperature is not particularly limited and may be generally performed under cool or heating conditions and preferably performed at a temperature from near room temperature to about 150° C. for 1 to 30 hours.

The compound (2) serving as a starting material for a compound according to the present invention include a novel compound and can be produced by various methods, for example, a method represented by the following reaction formula-3.

The compound (3) serving as a starting material for a compound according to the present invention is a known compound or a compound that can be easily produced from a known compound.

A salt of a compound (2) in place of the compound (2) and a salt of a compound (3) in place of the compound (3) may be used. The salts of compounds (2) and (3) include acid-addition salts. These acid addition salts may be prepared by reacting a pharmaceutically acceptable acid with a compound (2) or (3). Examples of the acid used herein include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, and hydrobromic acid; sulfonic acids such as p-toluene sulfonic acid, methane sulfonic acid, and ethane sulfonic acid; and organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, succinic acid, and benzoic acid.

Of the compounds (2), a compound having an acidic group can easily produce a salt by reacting with a pharmaceutically acceptable basic compound. Examples of such a basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide; alkali metal carbonates or bicarbonates such as sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; and alkali metal alcoholates such as sodium methylate and potassium ethylate.

wherein R¹, R² and A are the same as defined above; and X² is a hydroxy group, halogen atom or a group mediating the same substitution reaction as in a halogen atom.

Examples of the halogen atom represented by X² and the group mediating the same substitution reaction as in a halogen atom in connection with the general formula (4) are the same as mentioned above.

The compound (1) can be produced by reacting a compound (hereinafter referred to as a compound (4)) represented by the general formula (4) and a compound (hereinafter referred to as a “compound (5)”) represented by the general formula (5).

The reaction can be performed under the similar conditions as in reaction formula-1.

In the case of a compound (4) in which X² is a hydroxy group, the reaction can be performed in an appropriate solvent in the presence of an appropriate condensing agent.

This reaction is generally performed in a conventional solvent that may not negatively affect the reaction, such as water; an alcohol based solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; a ketone based solvent such as acetone and methylethyl ketone; an ether based solvent such as tetrahydrofuran, dioxane, diethyl ether, and diglyme; an ester based solvent such as methyl acetate and ethyl acetate; a non-proton polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethylsulfoxide; a halogenated hydrocarbon based solvent such as methylene chloride and ethylene chloride; or other organic solvents. Furthermore, as a solvent to be used herein, a solution mixture of these conventional solvents may be mentioned.

As the condensing agent, a mixture of an azocarboxylate such as diethyl azodicarboxylate and a phosphine compound such as triphenylphosphine may be mentioned.

The amount of the condensing agent used herein is generally at least equimolar, preferably equimolar to twice as large as that of a compound (4).

The ratio of a compound (4) to a compound (5) used in the reaction formula-2 may be generally at least equimole preferably about 2 times by mole.

The reaction temperature is not particularly limited and may generally be performed under cool or heating conditions, and preferably performed at a temperature from 0° C. to about 150° C. for 1 to 10 hours.

The compound (4) serving as a starting material for a compound according to the present invention is a known compound or a compound that can be easily produced from a known compound.

The compound (5) serving as a starting material for a compound according to the present invention include a novel compound and a compound that can be produced by various methods, for example, a method represented by the following reaction formula-4 or -5.

A salt of a compound (4) in place of the compound (4) and a salt of a compound (5) in place of the compound (5) may be used. As a preferable salt of a compound (4), the same salt as shown in a compound (2) may be mentioned. As a preferable salt of a compound (5), the same salt as shown in a compound (3) may be mentioned.

wherein R¹, X¹ and A are the same as defined above; and X³ is a halogen atom or a group mediating the same substitution reaction as in a halogen atom.

Examples of the halogen atom represented by X³ and the group mediating the same substitution reaction as in a halogen atom in connection with the general formula (7) are the same as mentioned above.

The compound (2) can be produced by reacting a compound (hereinafter referred to as a compound (6)) represented by the general formula (6) and a compound (hereinafter referred to as a compound (7)) represented by the general formula (7).

The reaction can be performed under the similar conditions as in reaction formula-1.

The compounds (6) and (7) serving as starting materials for a compound according to the present invention are known compounds or compounds that can be easily produced from known compounds.

In place of a compound (6), a salt of the compound (6) may be used. As a preferable salt of a compound (6), the same salt as shown in a compound (2) may be mentioned.

wherein R² and A are the same as defined above; and X⁴ is a halogen atom or a group mediating the same substitution reaction as in a halogen atom.

Examples of the halogen atom represented by X⁴ and the group mediating the same substitution reaction as in a halogen atom in connection with the general formula (8) are the same as mentioned above.

The compound (5) can be produced by reacting a compound (3) and a compound (hereinafter referred to as a compound (8)) represented by the general formula (8).

The reaction can be performed under the similar conditions as in reaction formula-1.

The compound (8) serving as a starting material for a compound according to the present invention is a known compound or a compound that can be easily produced from a known compound.

In place of a compound (3), a salt of the compound (3) may be used. As a preferable salt of a compound (3), the same salts as above may be mentioned.

wherein R² and A are the same as defined above; R⁴ is a lower alkanoyl group; and X⁴ is a halogen atom or a group mediating the same substitution reaction as in a halogen atom.

Examples of the lower alkanoyl group represented by R⁴ in the general formulas (9) and (10) are the same as mentioned above.

Furthermore, examples of the halogen atom represented by X⁴ and the group mediating the same substitution reaction as in a halogen atom in connection with the general formula (9) are the same as mentioned above.

A compound (hereinafter referred to as a compound (10)) represented by the general formula (10) can be produced by reacting a compound (3) and a compound (9).

The reaction can be performed under the similar conditions as in reaction formula-1.

The compound (9) serving as a starting material for a compound according to the present invention is a known compound or a compound that can be easily produced from a known compound.

In place of a compound (3), a salt of the compound (3) may be used. As a preferable salt of a compound (3), the same salts as above may be mentioned.

Subsequently, the compound (10) is subjected to a reaction for removing an acyl group to produce a compound (5).

As a preferable method of the reaction, a conventional reaction such as hydrolysis may be mentioned. The hydrolysis reaction may be preferably performed in the presence of a base or an acid including Lewis acid. Examples of the preferable base include inorganic salts such as an alkali metal (e.g., sodium and potassium), an alkaline metal hydrogen carbonate (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate), an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), an alkali metal carbonate (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), an alkali metal lower alkoxide (e.g., sodium methoxide and sodium ethoxide), and hydrides (e.g., sodium hydride and potassium hydride); and organic bases such as a trialkylamine (e.g., trimethylamine, triethylamine, and N-ethyl diisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, and DBU. As a preferable acid, mention can be made of organic acids (such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid) and inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide). The removal reaction using a Lewis acid such as a trihaloacetic acid (e.g., trichloroacetic acid and trifluoroacetic acid) may be preferably performed in the presence of a cation-trapping agent (e.g., anisole and phenol).

This reaction is generally performed in a conventional solvent that may not negatively affect the reaction, such as water; an alcohol based solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; a ketone based solvent such as acetone and methylethyl ketone; an ether based solvent such as tetrahydrofuran, dioxane, diethyl ether, and diglyme; an ester based solvent such as methyl acetate and ethyl acetate; a non-proton polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethylsulfoxide; a halogenated hydrocarbon based solvent such as methylene chloride and ethylene chloride; or other organic solvents. Furthermore, the reaction may be performed in a solution mixture of these conventional solvents. Of them, ethanol is preferable. The reaction temperature is not particularly limited and may generally be performed under cool or heating conditions, and preferably performed at near room temperature to near a boiling point of the solvent to be used for 0.5 to 75 hours.

In place of a compound (10), a salt of the compound (10) may be used. As a preferable salt of a compound (10), the same salt as shown in a compound (3) may be mentioned.

Furthermore, a compound (hereinafter referred to as a compound (5a)) where A of the compound (5) represents —CH₂A″- where A″ represents a C1 to C5 alkylene group can be produced by a method represented by the following reaction formula-6.

wherein R² is the same as defined above; and R³ is a lower alkoxy group. A″ represents a C1 to C5 alkylene group. The lower alkoxy group represented by R³ in the general formula (11) is the same as defined above.

Examples of the C1 to C5 alkylene group represented by A″ in the general formulas (11) and (5a) include a linear or branched alkylene group having 1 to 5 carbon atoms such as methylene, ethylene, methyl methylene, trimethylene, tetramethylene, 1-methyl trimethylene, 2-methyl trimethylene, 3-methyl tetramethylene, pentamethylene, and 2,2-dimethyl trimethylene.

The compound (5a) can be produced by subjecting a compound (hereinafter referred to as a compound (11)) represented by the general formula (11) to a reducing reaction.

The reaction can be performed by the method shown in Reference Example 6 or a similar method thereof. The reaction also can be performed by a conventional method using a reducing agent.

As a preferable reducing agent, mention may be made of a hydride (such as lithium aluminum hydride, sodium borohydride, lithium borohydride, diborane, and sodium cyanoborohydride).

This reaction is generally performed in a conventional solvent that may not negatively affect the reaction, such as an alcohol based solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; a ketone based solvent such as acetone and methylethyl ketone; an ether based solvent such as tetrahydrofuran, dioxane, diethyl ether, and diglyme; an ester based solvent such as methyl acetate and ethyl acetate; a non-proton polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethylsulfoxide; a halogenated hydrocarbon based solvent such as methylene chloride and ethylene chloride; or other organic solvents. Furthermore, the reaction may be performed in a solution mixture of these conventional solvents. The reaction temperature is not particularly limited and may generally be performed under cool or heating conditions, and preferably performed at near room temperature to near a boiling point of the solvent to be used for 0.5 to 75 hours.

The compound (11) serving as a starting material for a compound according to the present invention is a known compound or a compound that can be easily produced from a known compound.

In place of a compound (11), a salt of the compound (11) may be used. As a preferable salt of a compound (11), the same salt as shown in a compound (2) may be mentioned.

Furthermore, a compound (hereinafter referred to as a compound (11a)) where A″ of the compound (11) represents “—(CH₂)₂-” can be produced by a method represented by the following reaction formula-7.

where R² and R³ are the same as defined above.

The compound (11a) can be produced by reacting a compound (3) and a compound (hereinafter referred to as a compound (12)) represented by the general formula (12).

The reaction can be performed by the method shown in Reference Example 5 or a similar method thereof. This reaction is generally performed in a conventional solvent that may not negatively affect the reaction, such as water, an alcohol based solvent such as methanol, ethanol, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; a ketone based solvent such as acetone and methylethyl ketone; an ether based solvent such as tetrahydrofuran, dioxane, diethyl ether, and diglyme; an ester based solvent such as methyl acetate and ethyl acetate; a non-proton polar solvent such as acetonitrile, N,N-dimethylformamide, and dimethylsulfoxide; a halogenated hydrocarbon based solvent such as methylene chloride and ethylene chloride; or other organic solvents. Furthermore, the reaction may be performed in a solution mixture of these conventional solvents. The reaction temperature is not particularly limited and may generally be performed under cool or heating conditions, and preferably performed at near room temperature to near a boiling point of the solvent to be used for 0.5 to 75 hours.

The compound (12) serving as a starting material for a compound according to the present invention is a known compound or a compound that can be easily produced from a known compound.

A salt of a compound (3) in place of the compound (3) and a salt of a compound (12) in place of the compound (12) may be used. As a preferable salt of a compound (3), the same salt as shown above may be mentioned. As a preferable salt of a compound (12), the same salt as shown in a compound (2) may be mentioned.

The object compound obtained by each of the above reaction formula may form a suitable salt. Such suitable salts include the preferable salts of compound (1) exemplified below.

The preferable salts of compound (1) are pharmacologically acceptable salts and examples include metal salts such as alkali metal salts (for example, sodium salt potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, magnesium salt, etc.), salts of inorganic bases such as ammonium salt, alkaline metal carbonates (for example, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkaline metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium bicarbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); for example, salts of organic bases such as tri(lower)alkylamine (for example, trimethylamine, triethylamine, N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (for example, N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO); salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate.

In addition, compounds in the form in which solvate (for example, hydrate, ethanolate, etc.) was added to the starting compounds and object compound shown in each of the reaction formulae are included in each of the general formulas. As a preferable solvate, hydrate can be mentioned.

Each of the object compounds obtained by each of the general formulas can be isolated and purified from the reaction mixture by, for example, subjecting the reaction mixture to isolation operation such as filtration, concentration and extraction after cooling to separate a crude reaction product followed by conventional purification operation such as column chromatography or recrystallization.

The compound represented by the general formula (1) of the present invention naturally encompasses isomers such as geometrical isomer, stereoisomer and enantiomer.

A compound and a salt thereof represented by the general formula (1) may be used in the form of general pharmaceutical preparation. The preparation may be prepared by use of a diluent or an excipient such as a filler, extending agent, binder, humectant, disintegrator, surfactant, and lubricant. As a pharmaceutical preparation, various forms can be selected depending upon the therapeutic purpose. Typical forms thereof include a tablet, pill, powder, liquid, suspension, emulsion, granule, encapsulate, suppository, and injection (liquid, suspension).

In forming a tablet, a wide variety of types of carriers conventionally known in the art may be used. Examples of the carrier that may be used include an excipient such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicate; a binder such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatine solution, carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidine; a disintegrator such as dried starch, sodium alginate, powdered agar, powdered laminaran, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose; a disintegration suppressant such as saccharose, stearin, cocoa butter, and hydrogenated oil; a sorbefacient such as quaternary ammonium base and sodium lauryl sulfate; a humectant such as glycerin and starch; an adsorbing agent such as starch, lactose, kaolin, bentonite, and colloidal silica; and a lubricant such as refined talc, stearate, powdered boric acid, and polyethylene glycol. Furthermore, if necessary, a tablet may be coated with a general film. Examples of such a coated tablet include a sugar-coated tablet, gelatine encapsulated tablet, enteric-coated tablet, film coated tablet or double-layer tablet, and multi-layer tablet.

In forming a pill, a wide variety of types of carriers conventionally known in the art may be used. Examples of the carrier that may be used include an excipient such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin and talc; a binder such as powdered gum Arabic, powdered tragacanth, gelatine and ethanol; and a disintegrator such as laminaran and agar.

In forming a suppository, a wide variety of types of carriers conventionally known in the art may be used. Examples of the carrier that may be used include polyethylene glycol, cacao butter, higher alcohol, esters of a higher alcohol, gelatine, and semisynthetic glyceride.

A capsule is usually prepared by mixing an active ingredient compound with a carrier as illustrated above in accordance with a conventional method and filling the mixture in a hard gelatine capsule or a soft capsule.

In preparing an injection, a liquid agent, emulsion and suspension are preferably sterilized and isotonic with blood. When they are prepared into an injection, any diluent can be used as long as it is conventionally used as a diluent in the art. Examples of the diluent that may be used include water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters.

Note that, in this case, a pharmaceutical preparation may contain a salt, glucose or glycerin in a sufficient amount to prepare an isotonic solution. Alternatively, a general auxiliary solubilizer, buffer, soothing agent may be added. Furthermore, a pigment, preservative, aroma, flavor, sweetening agent and other medicinal substances may be added to a pharmaceutical preparation, if necessary.

The amount of a compound of the general formula (1) and a salt thereof to be contained in a pharmaceutical preparation according to the present invent is not particularly limited and appropriately selected from the wide range; however generally about 1 to 70 wt %, preferably about 1 to 30 wt % in a preparation composition.

A method of administrating a pharmaceutical preparation according to the present invention is not limited and administered by a method in accordance with the form of a preparation, the age, gender and other conditions of a patient, and severity of a disease. For example, in the case of a tablet, pill, liquid agent, suspension, emulsion, granule and capsule, it is perorally administrated. In addition, in the case of an injection, it is intravenously administered by itself or by mixing with a general replenisher such as glucose and amino acids, and, if necessary, it is solely administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. In the case of a suppository, it is administered into the rectum.

The dose of a pharmaceutical preparation according to the present invention is appropriately selected depending upon the dosage regimen (direction for use), age, gender and other conditions of a patient, and severity of a disease, etc.; however, the dose of an active ingredient compound may be generally and preferably set at about 0.1 to 10 mg/weight (kg) per day. It is desirable that an active ingredient compound be contained in the range of about 1 to 200 mg per dosage unit of a preparation.

Advantages of the Invention

A compound according to the present invention has a D₂ receptor partial agonist effect, 5-HT_(2A) receptor antagonist effect and serotonin uptake inhibitory effect.

The D₂ receptor partial agonist effect refers to an action which decelerates dopaminergic (DA) neurotransmission when it is enhanced, whereas accelerates dopaminergic (DA) neurotransmission when it is lowered. In this manner, the D₂ receptor partial agonist acts as a dopamine system stabilizer, which stabilizes DA neurotransmission into a normal state. By virtue of this effect, the compound of the present invention produces an excellent clinical improvement effect on symptoms caused by abnormal DA neurotransmission (acceleration or deceleration) without developing side effects. As the excellent clinical improvement effect, mention may be made of, effects of improving positive and negative symptoms, cognitive impairment and depressive symptom (see Michio Toru, Psychiatry, Vol. 46, page 855-864 (2004); Tetsuro Kikuchi and Hirose Takeshi, Brain Science, vol. 25, page 579-583 (2004); and Harrison, T. S, and Perry, C. M.: Drugs 64: 1715-1736, 2004).

5-HT_(2A) receptor antagonist effect refers to an action which reduces extrapyramidal side effects and develops a superior clinical response and more specifically effectively works for improving negative symptoms, cognitive impairment, depressive symptom, and insomnia (see Jun Ishigooka and Ken Inada: Japanese Journal of Clinical Psychopharmacology, vol. 4, page 1653-1664 (2001); Mitsukuni Murasaki: Japanese Journal of Clinical Psychopharmacology, vol. 1, page 5-22 (1998), and Meltzer, H. Y. et al.: Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).

The serotonin uptake inhibitory effect is, for example, effective in improving depressive symptoms (see Mitsukuni Murasaki: Japanese Journal of Clinical Psychopharmacology, vol. 1, page 5-22 (1998)).

The compound of the present invention is excellent in all these three effects or significantly excellent in one or two effects of them.

In addition, some of the compounds according to the present invention has an α₁ receptor antagonist effect in addition to the effects mentioned above. The α₁ receptor antagonist effect is effective in improving positive symptoms of schizophrenia (see Svensson, T. H.: Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003)

Therefore, a compound of the present invention has a wide treatment spectrum for schizophrenia and other central nervous system disorder and possesses a superior clinical response.

Accordingly, a compound of the present invention is extremely effective for improving various kinds of disorders of the central nervous system such as schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar disorder (for example, bipolar Type-I disorder and bipolar Type-II disorder); depression, endogenous depression, major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; anxiety disorder (for example, panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and acute stress disorder); somatoform disorder (for example, hysteria, somatization disorder, conversion disorder, pain disorder, and hypochondriasis), factitious disorder; dissociative disorder; sexual disorder (for example, sexual dysfunction, sexual desire disorder, sexual arousal disorder, and erectile dysfunction); eating disorder (for example, anorexia nervosa and bulimia nervosa); sleep disorder; adjustment disorder; substance-related disorder (for example, alcohol abuse; alcohol intoxication; drug addiction, stimulant intoxication, and narcotism); anhedonia (for example, iatrogenic anhedonia, anhedonia of a psychic or mental cause, anhedonia associated with depression, and anhedonia associated with schizophrenia); delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache); mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.

Furthermore, a compound of the present invention has few side effects, and excellent in tolerability and safety.

The starting compounds used in each of the above reaction formula may be suitable salt, the object compound obtained by each of the reaction may form a suitable salt. Such suitable salts include the preferable salts of compound (1) exemplified below.

The preferable salts of compound (1) are pharmacologically acceptable salts and examples include metal salts such as alkali metal salts (for example, sodium salt potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, magnesium salt, etc.), salts of inorganic bases such as ammonium salt, alkaline metal carbonates (for example, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkaline metal hydrogen carbonates (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium bicarbonate, etc.), alkali metal hydroxides (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); for example, salts of organic bases such as tri(lower)alkylamine (for example, trimethylamine, triethylamine, N-ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (for example, N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO); salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate.

In addition, compounds in the form in which solvate (for example, hydrate, ethanolate, etc.) was added to the starting compounds and object compound shown in each of the reaction formulae are included in each of the general formulas. As a preferable solvate, hydrate can be mentioned.

Each of the object compounds obtained by each of the general formulas can be isolated and purified from the reaction mixture by, for example, subjecting the reaction mixture to isolation operation such as filtration, concentration and extraction after cooling to separate a crude reaction product followed by conventional purification operation such as column chromatography or recrystallization.

The compound represented by the general formula (1) of the present invention naturally encompasses isomers such as geometrical isomer, stereoisomer and enantiomer.

The compound of the general formula (1) and a salt thereof can be used in a common form of pharmaceutical preparation. The pharmaceutical preparation is prepared by using usually used diluent or excipient such as filler, extending agent, binder, humectant, disintegrating agent, surfactant and lubricant. As for this pharmaceutical preparation, various forms can be selected depending on the purpose of treatment, and typical examples include a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, suppository, and injection (solution, suspension).

For shaping in tablet form, various materials conventionally well known as carrier in the art can be widely used. As examples, excipient such as lactose, saccharose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicate; binder such as water, ethanol, propanol, simple syrup, glucose solution, starch liquid, gelatine solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone; disintegrating agent such as dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegration preventing agent such as saccharose, stearin, cacao butter, hydrogenated oil; sorbefacient such as quaternary ammonium base, sodium lauryl sulfate; moisturizing agent such as glycerine, starch; absorbing agent such as starch, lactose, kaolin, bentonite, colloidal silica; lubricant such as purified talc, stearate, borate powder, polyethylene glycol can be used, for example. Furthermore, the tablet may be a tablet provided with conventional coating as required, for example, sugar-coated tablet, gelatine encapsulated tablet, enteric coating tablet, film coated tablet or double tablet, multilayer tablet.

For shaping in pill form, various materials conventionally well known as carrier in the art can be widely used. As examples, excipient such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; binder such as powdered gum arabic, powdered tragacanth, gelatine, ethanol; disintegrating agent such as laminaran, agar can be used, for example.

For shaping in suppository form, various materials conventionally well known as carrier can be widely used. Examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatine, semisynthesized glyceride, for example.

A capsule is usually prepared according to a conventional method by mixing active ingredient compounds with various carrier exemplified above and filling them into a hard gelatin capsule, a soft capsule or the like.

When prepared as injection liquid, it is preferable that solution, emulsion and suspension are sterilized and isotonic to the blood and for forming in these modes, any of those conventionally used in the art as diluent can be used, and, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, etc. can be used.

The pharmaceutical preparation may contain common salt, glucose or glycerine in an amount sufficient to prepare an isotonic solution in this case, and conventional solubilizer, buffer, soothing agent may be also added. Pigment, preservative, aromatic, flavor, sweetening and other pharmaceuticals may be further contained as required.

The amount of a compound of the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited but usually about 1 to 70% by weight in the preparation composition is suitable and preferably about 1 to 30% by weight.

There is not limitation in particular in the way of administration of the pharmaceutical preparation of the present invention and may be administered by a method in accordance with specific form of the preparation, age, sex and the other conditions of a patient, severity of disease, etc. For example, in the case of tablet, pill, solution, suspension, emulsion, granule and capsule, it is orally administered. In the case of injection, it is intravenously administered alone or in a mixture with conventional replacement fluid such as glucose and amino acids, and if necessary, and the preparation alone may be also administered intramuscularly, intracutaneously, subcutaneously or interperitoneally. It is administered in rectum in the case of suppository.

Applied dose of the pharmaceutical preparation of the present invention is appropriately selected in accordance with dosage regimen, age, sex and the other conditions of a patient, severity of disease, etc., but it is suitable that the amount of the active ingredient compound is usually about 0.1 to 10 mg per 1 kg of body weight per day. In addition, it is desirable that the active ingredient compound is contained in the preparation of a dosage unit form in the range of about 1 to 200 mg.

The compound of the present invention has D₂ receptor partial agonist effect, 5-HT_(2A) receptor antagonist effect and serotonin uptake inhibitory effect (or serotonin uptake inhibitory effect).

The D₂ receptor partial agonist effect suppresses dopaminergic (DA) neurotransmission when it is enhanced, and accelerates the DA neurotransmission when it is lowered and thus has a function to stabilize the DA neurotransmission to a normal state (dopamine system stabilizer). According to this function, excellent clinically improving effect on the conditions based on the DA abnormal neurotransmission (enhancement and lowering), for example, improving effect on positive and negative symptoms, improving effect on cognitive impairment, improving effect on depressive symptom, etc. are developed without developing side effects (See Michio Toru: Seishin-Igaku (Psychiatry), Vol. 46, pp. 855-864 (2004), Tetsuro Kikuchi and Tsuyoshi Hirose: Nou-no-Kagaku (Brain Science), Vol. 25, pp. 579-583 (2003) and Harrison, T. S, and Perry, C. M.: Drugs 64: 1715-1736, 2004).

5-HT_(2A) receptor antagonist effect reduces extrapyramidal side effects, develops superior clinical effects, and is effective for improvement of negative symptoms, improvement of cognitive impairment, improvement of depression condition, improvement of insomnia, for example (See Jun Ishigooka and Ken Inada: Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), Vol. 4, pp. 1653-1664 (2001), Mitsukuni Murasaki Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), Vol. 1, pp. 5-22 (1998), Puller, I. A. et al., Eur. J. Pharmacol., 407:39-46, 2000, and Meltzer, H. Y. et al, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1159-1172, 2003).

Serotonin uptake inhibitory effect (or serotonin reuptake inhibitory effect) is effective for improving depressive symptoms, for example (See Mitsukuni Murasaki: Rinsho-Seishin-Yakuri (Japanese Journal of Clinical Psychopharmacology), Vol. 1, pp. 5-22 (1998)).

The compounds of the present invention are excellent in all of these three effects, or remarkably excellent in one or two of these effects.

In addition, some of the compounds of the present invention have α₁ receptor antagonist effect in addition to the above-described effects. The α₁ receptor antagonist effect is effective for improving positive symptoms of schizophrenia (See Svensson, T. H.: Prog. Neuro-Psychopharmacol. Biol. Psychiatry 27: 1145-1158, 2003).

Therefore, the compounds of the present invention have a wide treatment spectrum for and excellent clinical effect on schizophrenia and other central nervous system disorders.

Accordingly, the compounds of the present invention are extremely effective for the treatment or prevention of central nervous system disorders including the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar disorder (for example, bipolar I type disorder and bipolar II type disorder); depression; endogenous depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; anxiety disorder (for example, panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.); somatoform disorder (for example, hysteria, somatization disorder, conversion disorder, pain disorder, hypochondriasis, etc.); factitious disorder; dissociative disorder; sexual disorder (for example, sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, etc.); eating disorder (for example, anorexia nervosa, bulimia nervosa, etc.); sleep disorder; adjustment disorder; substance-related disorder (for example, alcohol abuse, alcohol intoxication, drug addiction, stimulant intoxication, narcotism, etc.); anhedonia (for example, iatrogenic anhedonia, anhedonia of a psychic or mental cause, anhedonia associated with depression, anhedonia associated with schizophrenia, etc.); delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease, Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache); mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome.

Furthermore, the compounds of the present invention have little or no side effects and they are excellent in safety and tolerability.

A preferable example of a desired compound (1) is as follows:

where R² represents a hydrogen atom or a lower alkyl group; A represents a lower alkylene group or a lower alkenylene group (preferably a lower alkylene group); and R¹ represents a cyclo C3-C8 alkyl group, an aromatic group or a heterocyclic group selected from the group consisting of (I) to (IV) below:

(I) a cyclo C3-C8 alkyl group (more preferably a cyclohexyl group);

(II) an aromatic group selected from a phenyl group, naphthyl group, dihydroindenyl group and tetrahydronaphthyl group (more preferably a phenyl group);

(III) a saturated or unsaturated heteromonocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom and selected from the group consisting of a pyrrolidinyl group, imidazolidinyl group, piperidyl group, hexahydropyrimidinyl group, piperazinyl group, azepanyl group, azocanyl group, pyrrolyl group, dihydropyrrolyl group, imidazolyl group, dihydroimidazolyl group, triazolyl group, dihydrotriazolyl group, pyrazolyl group, pyridyl, dihydropyridyl group, pyrimidinyl group, dihydropyrimidinyl group, pyrazinyl group, dihydropyrazinyl group, pyridazinyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, oxazolidinyl group, isoxazolidinyl group, morpholinyl group, thiazolyl group, dihydrothiazolyl group, isothiazolyl group, thiadiazolyl group, dihydrothiazinyl group, thiazolidinyl group, tetrahydrofuryl group, tetrahydropyranyl group, pyranyl group, tetrahydrothiofuryl group, tetrahydrothiopyranyl group, thienyl group and thiopyranyl group (more preferably, a saturated or unsaturated heteromonocyclic group having 1 to 2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and selected from the group consisting of a pyrrolidinyl group, a piperidyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, an isoxazolyl group, a thiazolyl group, a pyranyl group and a thienyl group; and more preferably, a saturated or unsaturated heteromonocyclic group having 1 to 2 nitrogen atoms selected from the group consisting of a pyrrolidinyl group, a piperidyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group and a thiazolyl group; and

(IV) a benzene fused heterocyclic group that has 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom and that is selected from the group consisting of (1) a tetrahydroquinoxalinyl group, (2) a tetrahydroquinazolinyl group, (3) a dihydroquinazolinyl group, (4) an indolinyl group, (5) an indolyl group, (6) an isoindolinyl group, (7) a benzimidazolyl group, (8) a dihydrobenzimidazolyl group, (9) a tetrahydrobenzazepinyl group, (10) a tetrahydrobenzodiazepinyl group, (11) a hexahydrobenzazocinyl group, (12) a dihydrobenzoxazinyl group, (13) a dihydrobenzoxazolyl group, (14) a benzisoxazolyl group, (15) a benzoxadiazolyl group, (16) a tetrahydrobenzoxazepinyl group, (17) a dihydrobenzothiazinyl group, (18) a benzothiazolyl group, (19) a benzoxathiolyl group, (20) a chromenyl group, (21) a dihydrobenzofuryl group, (22) a carbazolyl group, (23) a dibenzofuryl group and (24) a quinoxalinyl group

wherein, on the cyclo C3-C8 alkyl group, the aromatic group and the heterocyclic group represented by R¹, 1 to 5 (more preferably 1 to 3) groups selected from the group consisting of the groups (1) to (66) below may be present as a substituent:

(1) a lower alkyl group,

(2) a lower alkenyl group,

(3) a halogen substituted lower alkyl group,

(4) a lower alkoxy group,

(5) a phenoxy group,

(6) a lower alkylthio group,

(7) a halogen substituted lower alkoxy group,

(8) a hydroxy group,

(9) a phenyl lower alkoxy group,

(10) a hydroxy lower alkyl group,

(11) a lower alkoxy lower alkyl group,

(12) a halogen atom,

(13) a cyano group,

(14) a phenyl aryl group,

(15) a nitro group,

(16) an amino group,

(17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group and a lower alkoxycarbonylamino lower alkanoyl group as a substituent(s) (more preferably an N-lower alkylamino group, N,N-di lower alkylamino group, N-lower alkanoylamino group, N-lower alkoxycarbonylamino group, N-lower alkylsulfonylamino group, N-lower alkyl-N-lower alkanoylamino group, N-lower alkyl-N-lower alkoxycarbonylamino group, N-[carbamoyl]amino group, N-[N-lower alkylcarbamoyl]amino group, N—[N,N-di lower alkylcarbamoyl]amino group, N-[amino lower alkanoyl]amino group, N—[[N-lower alkanoylamino]lower alkanoyl]amino group, or N—[[N-lower alkoxycarbonylamino]lower alkanoyl]amino group),

(18) a lower alkanoyl group,

(19) a phenyl sulfonyl group that may have a lower alkyl group on the phenyl group (more preferably a lower alkylphenylsulfonyl group),

(20) a carboxy group,

(21) a lower alkoxycarbonyl group,

(22) a carboxy lower alkyl group,

(23) a lower alkoxycarbonyl lower alkyl group,

(24) a lower alkanoylamino lower alkanoyl group,

(25) a carboxy lower alkenyl group,

(26) a lower alkoxycarbonyl lower alkenyl group,

(27) a carbamoyl lower alkenyl group that may have as a substituent(s) 1 to 2 groups selected from the group consisting of a lower alkyl group and a lower alkyl group substituted with 1 to 3 halogen atoms (more preferably a carbamoyl lower alkenyl group, an N-lower alkylcarbamoyl lower alkenyl group, an N,N-di lower alkylcarbamoyl lower alkenyl group or N-[a lower alkyl substituted with 1 to 3 halogen atoms]carbamoyl lower alkenyl),

(28) a carbamoyl group that may have 1 to 2 groups selected from the group consisting of the groups (i) to (lxxviii) below as a substituent(s):

(i) a lower alkyl group,

(ii) a lower alkoxy group,

(iii) a hydroxy lower alkyl group,

(iv) a lower alkoxy lower alkyl group,

(v) an phenyloxy lower alkyl group,

(vi) a halogen substituted lower alkyl group,

(vii) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group and a carbamoyl group (more preferably an N,N-di lower alkylamino lower alkyl group, an N-lower alkanoylamino lower alkyl group, an N-lower alkyl-N-lower alkanoylamino lower alkyl group, an N-lower alkyl-N-benzoylamino lower alkyl group, or an N-carbamoylamino lower alkyl group)

(viii) a cyclo C3-C8 alkyl group that may have 1 to 3 groups (preferably 1 to 2 groups, and more preferably 1 group) selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group and a phenyl lower alkoxy group as a substituent,

(ix) a cyclo C3-C8 alkyl substituted lower alkyl group,

(x) a lower alkenyl group,

(xi) a lower alkyl group having 1 to 2 carbamoyl groups which may have 1 to 2 groups (preferably 1 group) selected from the group consisting of a lower alkyl group, a phenyl group that may have a single lower alkyl group and a phenyl group that may have a single lower alkoxy group as a substituent(s) (more preferably a carbamoyl lower alkyl group, a dicarbamoyl lower alkyl group, an N-lower alkylcarbamoyl lower alkyl group, an N,N-di lower alkylcarbamoyl lower alkyl group, an N-[lower alkylphenyl]carbamoyl lower alkyl group, or an N-[lower alkoxyphenyl]carbamoyl lower alkyl group),

(xii) a lower alkyl group having 1 to 2 lower alkoxycarbonyl groups,

(xiii) a furyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the furyl group),

(xiv) a tetrahydrofuryl lower alkyl group,

(xv) a 1,3-dioxolanyl lower alkyl group,

(xvi) a tetrahydropyranyl lower alkyl group,

(xvii) a pyrrolyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the pyrrolyl group),

(xviii) a dihydropyrazolyl lower alkyl group that may have a single oxo group,

(xix) a pyrazolyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrazolyl group),

(xx) an imidazolyl lower alkyl group,

(xxi) a pyridyl lower alkyl group,

(xxii) a pyrazinyl lower alkyl group (that may have 1 to 3 (preferably 1) lower alkyl groups as a substituent on the pyrazinyl group),

(xxiii) a pyrrolidinyl lower alkyl group (that may have 1 to 2 groups selected from the group consisting of an oxo group and a lower alkyl group as a substituent(s) on the pyrrolidinyl group),

(xxiv) a piperidyl lower alkyl group (that may have 1 to 3 groups (preferably 1 group) selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent(s) on the piperidyl group),

(xxv) a piperazinyl lower alkyl group (that may have 1 to 3 (preferably 1) lower alkyl groups as a substituent(s) on the piperazinyl group),

(xxvi) a morpholinyl lower alkyl group,

(xxvii) a thienyl lower alkyl group (that may have 1 to 3 (preferably 1) lower alkyl group as a substituent(s) on the thienyl group),

(xxviii) a thiazolyl lower alkyl group,

(xxix) a dihydrobenzofuryl lower alkyl group,

(xxx) a benzopyranyl lower alkyl group (that may have a single oxo group as a substituent on the benzopyranyl group),

(xxxi) a benzimidazolyl lower alkyl group,

(xxxii) an indolyl lower alkyl group that may have 1 to 3 (preferably 1) lower alkoxycarbonyl groups on the lower alkyl group),

(xxxiii) an imidazolyl lower alkyl group that has 1 to 3 substituents (preferably 1 substituent) selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group on the lower alkyl group,

(xxxiv) a pyridyl group that may have 1 to 3 groups (preferably 1 group) selected from the group consisting of a lower alkyl group, a lower alkoxy group and a lower alkylthio lower alkyl group as a substituent(s),

(xxxv) a pyrrolidinyl group that may have 1 to 3 groups (preferably 1 group) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group and a benzoyl group as a substituent,

(xxxvi) a piperidyl group that may have 1 to 3 groups (preferably 1 group) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group and a benzoyl group that may have 1 to 3 groups (preferably 1 group) selected from the group consisting of a lower alkyl group and a halogen atom on the phenyl group,

(xxxvii) a tetrahydrofuryl group that may have a single oxo group,

(xxxviii) a hexahydroazepinyl group that may have a single oxo group,

(xxxix) a pyrazolyl group that may have 1 to 3 groups (preferably 1 group) selected from the group consisting of a lower alkyl group, a phenyl group and a furyl group as a substituent,

(xl) a thiazolyl group,

(xli) a thiadiazolyl group that may have 1 to 3 (preferably 1) lower alkyl groups,

(xlii) an isoxazolyl group that may have 1 to 3 (preferably 1 to 2) lower alkyl groups,

(xliii) an indazolyl group,

(xliv) an indolyl group,

(xlv) a tetrahydrobenzothiazolyl group,

(xlvi) a tetrahydroquinolyl group that may have 1 to 3 (preferably 1 to 2) groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and an oxo group as a substituent,

(xlvii) a quinolyl group that may have 1 to 3 (preferably 1) lower alkyl groups,

(xlviii) a benzodioxolyl lower alkyl group,

(xlix) a phenyl group or naphthyl group that may have 1 to 3 groups as a substituent(s), selected from the group consisting of

a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; a phenyloxy group; a phenyl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have a group selected from the group consisting of a lower alkyl group and a phenyl group; a pyrazolyl group; a pyrrolidinyl group that may have a single oxo group; an oxazolyl group; an imidazolyl group that may have 1 to 3 (preferably 1 to 2) lower alkyl groups; a dihydrofuryl group that may have a single oxo group; a thiazolidinyl lower alkyl group that may have two oxo groups; an imidazolyl lower alkanoyl group and a piperidinylcarbonyl group,

(l) a cyano lower alkyl group,

(li) a dihydroquinolyl group that may have 1 to 3 (more preferably 1 to 2) groups selected from the group consisting of a lower alkyl group and an oxo group,

(lii) a halogen substituted lower alkylamino group,

(liii) a lower alkylthio lower alkyl group,

(liv) an amidino group that may have 1 to 2 lower alkyl groups,

(lv) an amidino lower alkyl group,

(lvi) a lower alkenyloxy lower alkyl group,

(lvii) a phenyl amino group that may have 1 to 3 substituents (more preferably 1 substituent) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group and a halogen substituted lower alkoxy group on the phenyl group,

(lviii) a phenyl lower alkenyl group,

(lix) a pyridylamino group that may have 1 to 3 (more preferably 1 to 2) lower alkyl groups (more preferably N-lower alkyl-N-[lower alkylpyridyl]amino group),

(lx) a phenyl lower alkyl group (that may have 1 to 3 groups (more preferably 1 to 2 groups) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, a carbamoyl group and a lower alkoxycarbonyl group as a substituent on the phenyl group and/or the lower alkyl group),

(lxi) a lower alkynyl group,

(lxii) a phenyloxy lower alkyl group (that may have as a substituent(s) on the phenyl group 1 to 3 groups (preferably 1 group) selected from the group consisting of a lower alkoxy group, an N-lower alkoxy-N-lower alkylcarbamoyl group and an oxopyrrolidinyl group),

(lxiii) an isoxazolidinyl group that may have a single oxo group,

(lxiv) a dihydroindenyl group,

(lxv) a phenyl lower alkoxy lower alkyl group,

(lxvi) a tetrahydropyranyl group,

(lxvii) an azetidinyl group that may have 1 to 3 groups (more preferably 1 group) selected from the group consisting of a lower alkanoyl group and a benzoyl group,

(lxviii) an azetidinyl lower alkyl group that may have 1 to 3 groups (more preferably 1 group) selected from the group consisting of a lower alkanoyl group and a benzoyl group,

(lxix) a tetrazolyl group,

(lxx) an indolinyl group that may have a single oxo group,

(lxxi) a triazolyl group that may have 1 to 3 groups (more preferably 1 to 2 groups) selected from the group consisting of a lower alkyl group and a lower alkylthio group,

(lxxii) an imidazolyl group that may have 1 to 3 (more preferably 1) carbamoyl groups,

(lxxiii) an oxazolyl group that may have 1 to 3 (more preferably 1) lower alkyl groups,

(lxxiv) an isothiazolyl group that may have 1 to 3 (more preferably 1) lower alkyl groups,

(lxxv) a benzimidazolyl group,

(lxxvi) a dihydrobenzothiazolyl group that may have a single oxo group,

(lxxvii) a thienyl group that may have 1 to 3 (more preferably 1) lower alkoxycarbonyl groups, and

(lxxviii) an oxazolyl lower alkyl group that may have 1 to 3 (more preferably 1 to 2) lower alkyl groups

(29) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a benzoyl group and an amino substituted alkyl group (that may have 1 to 2 (more preferably 2) lower alkyl groups as a substituent(s) on the amino group) on the amino group,

(30) a lower alkyl group substituted with a single carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group,

(31) a thiocarbamoyl group that may have 1 to 2 (more preferably 1) lower alkyl group,

(32) a sulfamoyl group,

(33) an oxazolidinyl group that may have a single oxo group (more preferably an oxazolidinyl group substituted with a single oxo group),

(34) an imidazolidinyl group that may have 1 to 2 substituents selected from the group consisting of an oxo group and a lower alkyl group,

(35) a pyrrolidinyl group that may have a single oxo group,

(36) an imidazolyl group,

(37) a triazolyl group,

(38) an isoxazolyl group,

(39) a piperidyl group that may have 1 to 3 (more preferably 1 to 2, and still more preferably 1) substituents selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkylphenylsulfonyl group, an oxo group, a hydroxy group, and amino group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group and lower alkanoylamino lower alkanoyl group (more preferably a piperidyl group that may have 1 to 3 (more preferably 1 to 2, and still more preferably 1) substituents selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkylphenylsulfonyl group, an oxo group, a hydroxy group, an amino group, an N-lower alkylamino group, an N,N-di lower alkylamino group, an N-lower alkanoylamino group, an N-lower alkyl-N-lower alkoxycarbonylamino group, an N-lower alkyl-N-lower alkanoylamino group, and an N-lower alkanoylamino lower alkanoylamino group),

(40) a piperidylcarbonyl group that may have 1 to 3 (more preferably 1 to 2) substituents selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group and a benzoyl group may be present), a piperidyl group (on which 1 to 3 groups (more preferably 1 group) selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group and a benzoyl group may be present), a piperazinyl group (on which 1 to 3 (more preferably 1 to 2) lower alkyl groups may be present as a substituent), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepinyl group (on which a single lower alkyl group may be present as a substituent), pyridyl group, pyridyloxy group, pyridyl lower alkoxy group, tetrahydroquinolyl group (on which a single oxo group may be present), benzodioxolyl group, phenyl lower alkoxy group (that may have 1 to 3 groups (more preferably 1 to 2 groups) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkoxy group on the phenyl group), phenyl group (on which 1 to 3 groups (preferably 1 to 2 groups) selected from the group consisting of a halogen atom, a lower alkoxy group and a hydroxy group may be present), a phenyloxy group (that may have on the phenyl group 1 to 3 groups (preferably 1 to 2 groups) selected from the group consisting of a cyano group, a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkyl group), a phenyl lower alkyl group (that may have on the phenyl group 1 to 3 groups (more preferably 1 to 2 groups) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and a halogen substituted lower alkyl group), and a benzoyl group (that may have on the phenyl group 1 to 3 groups (more preferably 1 to 2 groups) selected from the group consisting of a halogen atom and a lower alkoxy group),

(41) a pyrrolidinylcarbonyl group that may have 1 to 3 (more preferably 1) groups as a substituent, selected from the group consisting of a hydroxy lower alkyl group, a carbamoyl group, a hydroxy group, an amino group (that may have on the amino group 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group and a benzoyl group), morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a single lower alkyl group as a substituent on the piperazinyl group), an amino lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent on the amino group), phenyloxy group (that may have 1 to 3 (more preferably 1) halogen substituted lower alkoxy groups on the phenyl group), a phenyloxy lower alkyl group (that may have 1 to 3 (more preferably 1) halogen substituted lower alkoxy groups on the phenyl group) and a tetrahydroquinolyl group (on which an oxo group may be present),

(42) a piperazinylcarbonyl group that may have 1 to 3 groups (more preferably 1 to 2 groups), as a substituent, selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent on the amino group), piperidyl lower alkyl group (that may have 1 to 2 (more preferably 1) lower alkyl groups as a substituent(s) on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxolanyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have 1 to 2 (more preferably 1) phenyl groups as a substituent(s) on the lower alkyl group), an imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group that may have 1 to 2 (more preferably 1) lower alkyl groups as a substituent(s), a pyridyl group (that may have on the pyridyl group 1 to 3 groups (more preferably 1 group) selected from the group consisting of a lower alkyl group, a cyano group and a halogen substituted lower alkyl group as a substituent), a thieno[2,3-b]pyridyl group, a phenyl group (on which 1 to 3 groups (more preferably 1 group) selected from the group consisting of a halogen atom and a lower alkyl group may be present), a benzoyl group, a furyl carbonyl group, a phenyl lower alkoxycarbonyl group and an oxo group,

(43) a hexahydroazepinylcarbonyl group,

(44) a hexahydro-1,4-diazepinylcarbonyl group that may have 1 to 3 substituents (more preferably 1 substituent) selected from the group consisting of a lower alkyl group and a pyridyl group,

(45) a dihydropyrrolylcarbonyl group that may have 1 to 3 (more preferably 1 to 2) lower alkyl groups,

(46) a thiomorpholinylcarbonyl group,

(47) a morpholinylcarbonyl group that may have 1 to 3 groups (more preferably 1 group) selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group and a phenyl group,

(48) a thiazolidinyl carbonyl group that may have 1 to 3 (more preferably 1) phenyl groups that may have 1 to 3 groups (more preferably 1 group) selected from the group consisting of a lower alkoxy group and a cyano group,

(49) an azabicyclo[3.2.2]nonylcarbonyl group,

(50) an 8-azabicyclo[3.2.1]octylcarbonyl group that may have 1 to 3 (more preferably 1) halogen substituted or unsubstituted phenyloxy groups,

(51) an indolinylcarbonyl group,

(52) a tetrahydroquinolylcarbonyl group,

(53) a tetrahydropyrido[3.4-b]indolylcarbonyl group,

(54) a morpholinyl lower alkyl group,

(55) a piperazinyl lower alkyl group that may have 1 to 3 (more preferably 1) lower alkyl groups on the piperazinyl group,

(56) a morpholinylcarbonyl lower alkyl group,

(57) a piperazinylcarbonyl lower alkyl group that may have 1 to 3 (more preferably 1) lower alkyl groups on the piperazinyl group,

(58) an oxo group,

(59) an amino lower alkoxy group (that may have 1 to 2 (more preferably 2) lower alkyl groups on the amino group),

(60) a lower alkoxy lower alkoxy group,

(61) a piperazinyl group that may have 1 to 3 groups (more preferably 1 to 2 groups) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group and a lower alkoxycarbonyl group (more preferably, a piperazinyl group substituted with a single oxo group, a piperazinyl group substituted with a single lower alkyl group, a piperazinyl group substituted with a single lower alkanoyl group, a piperazinyl group substituted with a single oxo group and a single lower alkanoyl group, and a piperazinyl group substituted with a single oxo group and a single lower alkoxy carbonyl group),

(62) a morpholinyl group,

(63) a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have 1 to 3 groups (more preferably 1 to 2 groups) selected from the group consisting of an oxo group and a phenyl group,

(64) a tetrahydropyridylcarbonyl group that may have 1 to 3 (more preferably 1) pyridyl groups,

(65) an imidazolidinylcarbonyl group that may have one thioxo group, and

(66) a 1,4-dioxa-8-azaspiro[4.5]decanyl group.

In the general formula (1), R¹ is preferably a cyclohexyl group, phenyl group, pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, or thiazolyl group. The ring of each groups is preferably substituted with 1 to 3 groups selected from the group consisting of:

(1) a lower alkyl group,

(4) a lower alkoxy group,

(10) a hydroxy lower alkyl group,

(17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxy carbonyl group, a lower alkyl sulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group and a lower alkoxycarbonylamino lower alkanoyl group as a substituent(s),

(21) a lower alkoxycarbonyl group,

(28) a carbamoyl group that may have 1 to 2 substituents selected from the group consisting of the groups (i), (ii), (iv), (xii) and (xxi) below:

(i) a lower alkyl group,

(ii) a lower alkoxy group,

(iv) a lower alkoxy lower alkyl group,

(xii) a lower alkyl group having 1 to 2 lower alkylcarbonyl groups,

(xxi) a pyridyl lower alkyl group,

(29) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a benzoyl group and an amino substituted alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the amino group) on the amino group,

(30) a lower alkyl group substituted with a single carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group,

(33) an oxazolidinyl group that may have a single oxo group,

(34) an imidazolidinyl group that may have 1 to 2 substituents selected from the group consisting of an oxo group and a lower alkyl group,

(35) a pyrrolidinyl group that may have a single oxo group,

(36) an imidazolyl group,

(39) a piperidyl group that may have a single substituent selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkyl phenylsulfonyl group, an oxo group, a hydroxy group, an amino group, an N-lower alkylamino group, an N—N di-lower alkyl amino group, an N-lower alkanoylamino group, an N-lower alkyl-N-lower alkoxycarbonylamino group, an N-lower alkyl-N-lower alkanoylamino group, and an N-lower alkanoylamino lower alkanoylamino group,

(61) a piperazinyl group that may have 1 to 2 groups selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group and a lower alkoxy carbonyl group, and

(62) a morpholinyl group.

EXAMPLE

Hereinbelow, the present invention will be further made clear with reference to Reference Examples, Examples and Pharmacological Experimental Examples and Preparation Examples.

Reference Example 1 Synthesis of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride

A mixture consisting of 14.4 g of 4-bromobenzo[b]thiophene, 29.8 g of piperazine anhydride, 9.3 g of sodium t-butoxide, 0.65 g of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), 0.63 g of tris(dibenzylideneacetone)dipalladium (0) and 250 ml of toluene was refluxed with heating for one hour under a nitrogen atmosphere. Water was poured to the reaction solution, which was then extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol:25% ammonia water=100:10:1), to obtain 9.5 g of 1-benzo[b]thiophen-4-yl-piperazine in the form of yellow oil.

Then, 3.7 ml of concentrated hydrochloric acid was added to a methanol solution of 9.5 g of 1-benzo[b]thiophen-4-yl-piperazine, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue and precipitated crystals were obtained by filtration. Recrystallization was performed from methanol to obtain 1-benzo[b]thiophen-4-yl-piperazine hydrochloride as colorless needle-like crystals.

Melting point 276-280° C.

¹H-NMR (DMSO-d₆) δppm: 3.25-3.35 (8H, m), 6.94 (1H, d, J=7.6 Hz), 7.30 (1H, dd, J=7.8 Hz, J=7.8 Hz), 7.51 (1H, d, J=5.5 Hz), 7.68 (1H, d, J=8.1 Hz), 7.73 (1H, d, J=5.5 Hz), 9.35 (2H, brs).

Reference Example 2 Synthesis of tert-butyl 4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate

The titled compound was obtained using tert-butyl 3-methylpiperazin-1-carboxylate and 4-bromobenzo[b]thiophene in the same manner as in Reference Example 1.

¹H-NMR (CDCl₃) δppm: 1.85-1.95 (3H, m, 1.50 (9H, s, 2.8-2.9 (1H, m), 3.15-3.35 (2H, m), 3.4-3.5 (1H, m), 3.5-3.65 (1H, m), 3.65-3.7 (1H, m), 3.7-3.9 (1H, m), 6.98 (1H, d, J=7.5 Hz), 7.29 (1H, dd, J=8 Hz, J=8 Hz), 7.38 (1H, d, J=5.5 Hz), 7.61 (1H, d, J=8 Hz).

Reference Example 3 Synthesis of 1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride

Trifluoroacetic acid (6 ml) was added to a solution of 1.22 g (3.7 mmol) of tert-butyl 4-benzo[b]thiophen-4-yl-3-methylpiperazin-1-carboxylate in a dichloromethane solution (12 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous potassium carbonate solution was added to the residue and the resulting mixture was extracted with dichloromethane. The extraction solution with dichloromethane was dried over magnesium sulfate and thereafter concentrated under reduced pressure. To the residue obtained, concentrated hydrochloric acid (0.6 ml) and methanol (10 ml) were added and the resulting mixture was concentrated under reduced pressure. The obtained residue was subjected to recrystallization from acetonitrile to obtain 1-benzo[b]thiophen-4-yl-2-methylpiperazine dihydrochloride (0.98 g) as light brown powder.

¹H-NMR (DMSO-d₆) δppm: 0.92 (3H, d, J=6.5 Hz), 2.8-3.6 (6H, m), 3.6-4.0 (1H, m), 5.3-6.8 (1H, m), 7.20 (1H, br), 7.38 (1H, dd, J=8 Hz, J=8 Hz), 7.5-8.0 (3H, m), 9.4-10.1 (2H, m).

Reference Example 4 Synthesis of 1-benzo[b]thiophen-4-yl-3-methylpiperazine dihydrochloride

The titled compound was obtained using 2-methylpiperazine and 4-bromobenzo[b]thiophene in the same manner as in Reference Example 1.

¹H-NMR (DMSO-d₆) δppm: 1.34 (3H, d, J=6.5 Hz), 2.85-2.95 (1H, m), 3.05-3.15 (1H, m), 3.2-3.6 (6H, m), 6.97 (1H, d, J=7.5 Hz), 7.31 (1H, dd, J=8 Hz, J=8 Hz), 7.54 (1H, d, J=5.5 Hz), 7.69 (1H, d, J=8 Hz), 7.75 (1H, d, J=5.5 Hz), 9.2-9.3 (1H, m), 9.64 (1H, br).

Reference Example 5 Synthesis of ethyl 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate

5.05 g (19.8 mmol) of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride was added to an aqueous solution of sodium hydroxide, and the mixture was extracted with dichloromethane. The extraction solution was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of ethanol and ethyl acrylate (2.44 ml, 21.8 mmol) was added thereto, and then the reaction mixture was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Diisopropyl ether was added to the residue and insoluble matter precipitated was obtained by filtration, washed with diisopropyl ether, and dried to obtain ethyl 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate (5.26 g) as white powder.

¹H-NMR (CDCl₃) δppm: 1.28 (3H, t, J=7.0 Hz), 2.50-2.63 (2H, m), 2.67-2.87 (6H, m), 3.11-3.24 (4H, m), 4.17 (2H, q, J=7.0 Hz), 6.89 (1H, d, J=7.8 Hz), 7.27 (1H, t, J=7.8 Hz), 7.37-7.42 (2H, m), 7.55 (1H, d, J=7.8 Hz).

Reference Example 6 Synthesis of 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol

Lithium aluminum hydride (1.18 g, 24.8 mmol) was added to a solution of 5.26 g (16.5 mmol) of ethyl 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate in a tetrahydrofuran (THF) solution (55 ml) under ice cooling, and the mixture was stirred at room temperature for 4 hours. To the reaction solution, water (1.2 ml), 15% aqueous sodium hydroxide solution (1.2 ml), and water (3.6 ml) were added in this order and the mixture was stirred at room temperature. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2→3 ethyl acetate) and concentrated to dryness under reduced pressure to obtain 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol (0.23 g) as white powder.

¹H-NMR (CDCl₃) δppm: 1.75-1.85 (2H, m), 2.74 (2H, t, J=5.8 Hz), 2.75-2.85 (4H, m), 3.15-3.25 (4H, m), 3.85 (2H, t, J=5.3 Hz), 5.19 (1H, brs), 6.88 (1H, d, J=7.6 Hz), 7.27 (1H, dd, J=7.9 Hz, J=7.8 Hz), 7.39 (2H, s), 7.56 (1H, d, J=8.0 Hz).

Reference Example 7 Synthesis of 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate

1.0 g (3.9 mmol) of 1-benzo[b]thiophen-4-yl-piperazine hydrochloride was suspended in 20 ml of dimethylformamide (DMF), and potassium carbonate (1.3 g, 9.4 mmol) and 4-bromobutyl acetate (0.7 ml, 4.8 mmol) were added thereto. The reaction mixture was stirred at 80° C. for 6 hours, cooled to room temperature, and water was added thereto, and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), and concentrated to dryness under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate (0.72 g) as light yellow oil.

¹H-NMR (CDCl₃) δppm: 1.60-1.73 (4H, m), 2.07 (3H, s), 2.47 (2H, t, J=7.2 Hz), 2.60-2.72 (4H, m), 3.17-3.22 (4H, m), 4.11 (2H, t, J=6.3 Hz), 6.90 (1H, d, J=7.6 Hz), 7.27 (1H, dd, J=7.6 Hz, J=8.0 Hz), 7.37-7.42 (2H, m), 7.55 (1H, d, J=8.0 Hz).

Reference Example 8 Synthesis of 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butan-1-ol

Potassium carbonate (3.87 g, 28 mmol) was added to a solution of 7.76 g (23.3 mmol) of 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate in 90% methanol solution (150 ml). The solution mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. The extraction solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), and concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butan-1-ol (6.65 g) as colorless oil.

¹H-NMR (CDCl₃) δppm: 1.60-1.74 (4H, m), 2.50-2.55 (2H, m), 2.70-2.80 (4H, m), 3.20-3.30 (4H, m), 3.60-3.63 (2H, m), 6.2 (1H, brs), 6.90 (1H, d, J=7.6 Hz), 7.27 (1H, dd, J=7.6 Hz, J=8.0 Hz), 7.39 (1H, s), 7.56 (1H, d, J=8.0 Hz).

Reference Example 9 Synthesis of 1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine

3.56 g (12.9 mmol) of 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propan-1-ol was suspended in 30 ml of dichloromethane, and carbon tetrachloride (30 ml) and triphenyl phosphine (4.06 g, 15.5 mmol) were added thereto. The mixture was refluxed with heating for 3 hours. The reaction solution was cooled to room temperature, then methanol and dichloromethane were added thereto to homogenize the mixture. Silica gel (30 g) was added to the solution, and the solvent was evaporated under reduced pressure. The obtained residue was loaded on silica gel column (300 g) and extracted with a solvent mixture of n-hexane:ethyl acetate=2:1. The extraction solution was concentrated under reduced pressure to obtain 1-benzo[b]thiophen-4-yl-4-(3-chloropropyl)piperazine (2.36 g) as colorless oil.

¹H-NMR (CDCl₃) δppm: 1.95-2.10 (2H, m), 2.60 (2H, t, J=7.2 Hz), 2.65-2.75 (4H, m), 3.15-3.25 (4H, m), 3.65 (2H, t, J=6.6 Hz), 6.89 (1H, dd, J=7.6 Hz, J=0.7 Hz), 7.27 (1H, dd, J=7.9 Hz, J=7.8 Hz), 7.38 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=5.7 Hz), 7.55 (1H, d, J=8.0 Hz).

Reference Example 10 Synthesis of methyl 4-hydroxythiophene-2-carboxylate

Thionyl chloride (1.6 ml) was added dropwise to a methanol solution (20 ml) of 4-hydroxythiophene-2-carboxylic acid (1.1 g, 7.6 mmol) under ice cooling. The solution mixture was refluxed with heating for 5 hours. The reaction solution was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) and concentrated/dried under reduced pressure to obtain methyl 4-hydroxythiophene-2-carboxylate (0.7 g) as white powder.

¹H-NMR (CDCl₃) δppm: 3.90 (3H, s), 5.50-6.60 (1H, br), 6.64 (1H, d, J=1.9 Hz), 7.43 (1H, d, J=1.8 Hz).

Reference Example 11 Synthesis of ethyl 6-hydroxypyrimidine-4-carboxylate

The titled compound was obtained using 6-hydroxypyrimidine-4-carboxylic acid in the same manner as in Reference Example 10.

¹H-NMR (CDCl₃) δppm: 1.29 (3H, t, J=7.0 Hz), 4.29 (2H, q, J=7.0 Hz), 6.87 (1H, d, J=1.0 Hz), 8.27 (1H, d, J=1.0 Hz), 10.54 (1H, br).

Reference Example 12 Synthesis of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate

A diethyl ether solution (35 ml) of dimethyl acetylenedicarboxylate (5.0 g, 35 mmol) was cooled with a freezing medium (salt & ice). To this solution, a diethyl ether solution (15 ml) of methyl hydrazine (0.63 ml, 35 mmol) was added dropwise while maintaining the temperature at 0° C. or less. After completion of dropwise addition, the solution was stirred at 0° C. for one hour. The insoluble matter precipitated was obtained by filtration and washed with diethyl ether. The filter cake was heated to 130° C. for 30 minutes and cooled to room temperature. Methanol was added to the cake, which was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue and the residue was concentrated under reduced pressure. Ethyl acetate was added to the residue and the insoluble matter precipitated was obtained by filtration, washed with ethyl acetate, and dried to obtain methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (3.26 g) as light yellow powder.

¹H-NMR (DMSO-d₆) δppm: 3.58 (3H, s), 3.73 (3H, s), 5.77 (1H, s), 11.41 (1H, br).

Reference Example 13 Synthesis of 6-chloro-N-(2,2,2-trifluoroethyl)nicotine amide

Triethylamine (1.03 ml, 7.4 mmol) and isobutyl chloroformate (0.76 ml, 5.5 mmol) were added to an acetonitrile solution (12 ml) of 6-chloronicotinic acid (0.58 g, 3.6 mmol) under ice cooling and the mixture was stirred at 0° C. for 30 minutes. To the solution mixture, 2,2,2-trifluoroethyl amine (0.88 ml, 11.2 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1). The purified product was concentrated under reduced pressure and diisopropyl ether and n-hexane were added. The insoluble matter precipitated was obtained by filtration and dried to obtain 6-chloro-N-(2,2,2-trifluoroethyl)nicotine amide (0.58 g) as light yellow powder.

¹H-NMR (CDCl₃) δppm: 4.15 (2H, dq, J=6.5 Hz, 9.0 Hz), 6.35 (1H, br), 7.46 (1H, dd, J=0.7 Hz, J=8.5 Hz), 8.11 (1H, dd, J=2.5 Hz, J=8.5 Hz), 8.77 (1H, dd, J=0.7 Hz, J=2.5 Hz).

Reference Example 14 Synthesis of N-(2,2,2-trifluoroethyl)-4-chloropyridine-2-carboxamide

1-hydroxybenzotriazole (0.53 g, 3.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.67 g, 3.5 mmol) and 2,2,2-trifluoroethyl amine (0.51 ml. 6.35 mmol) were added to a dichloromethane solution (5 ml) of 4-chloropyridine-2-carboxylic acid (0.5 g, 3.17 mmol) and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=11:1→5:1). The purified product was concentrated to dryness under reduced pressure to obtain N-(2,2,2-trifluoroethyl)-4-chloropyridine-2-carboxamide (435 mg) as white powder.

¹H-NMR (CDCl₃) δppm: 4.13 (2H, dq, J=6.8 Hz, 9.0 Hz), 7.49 (1H, dd, J=2.1 Hz, J=5.3 Hz), 8.22 (1H, dd, J=0.4 Hz, J=2.1 Hz), 8.30 (1H, br), 8.49 (1H, dd, J=0.4 Hz, J=5.3 Hz).

Reference Example 15 Synthesis of 2-chlorothiazole-4-carboxamide

1-hydroxybenzotriazole (0.56 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.7 g, 3.7 mmol) and ammonia water (28%, 0.5 ml)) were added to a dichloromethane solution (10 ml) of 2-chlorothiazole-4-carboxylic acid (0.5 g, 3.06 mmol) and the mixture was stirred at room temperature for 46 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:5→ethyl acetate). The purified product was concentrated to dryness under reduced pressure to obtain 2-chlorothiazole-4-carboxamide (475 mg) as white powder.

¹H-NMR (CDCl₃) δppm: 5.70 (1H, br), 7.01 (1H, br), 8.06 (1H, s).

Reference Example 16 Synthesis of N-methyl-2-chlorothiazole-5-carboxamide

The titled compound was obtained using 2-chlorothiazole-5-carboxylic acid in the same manner as in Reference Example 13.

¹H-NMR (CDCl₃) δppm: 3.00 (3H, d, J=4.9 Hz), 5.92 (1H, br), 7.84 (1H, br).

Reference Example 17 Synthesis of 6-methoxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one

5% palladium carbon (1.5 g) were added to an ethanol solution (250 ml) of ethyl 2-(4-methoxy-2-nitrophenoxy)-2-methylpropionate (14.6 g, 51.6 mmol) to perform catalytic reduction at room temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue, which was then extracted with ethyl acetate. The extraction solution was dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated to dryness under reduced pressure to obtain 6-methoxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (7.0 g) as white powder.

¹H-NMR (CDCl₃) δppm: 1.53 (6H, s), 3.78 (3H, s), 6.40 (1H, d, J=2.8 Hz), 6.52 (1H, dd, J=2.8 Hz, J=8.8 Hz), 6.88 (1H, d, J=8.7 Hz), 8.66 (1H, brs).

Reference Example 18 Synthesis of 6-hydroxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one

A dichloromethane solution (36 ml) of 2M boron tribromide was added dropwise to a dichloromethane solution of 6-methoxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (5.0 g, 26 mmol) under ice cooling and the mixture was stirred overnight. Water was added to the reaction solution to decompose the reagents excessively present. The reaction solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1). The purified product was concentrated to dryness under reduced pressure to obtain 6-hydroxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (4.02 g) as white powder.

¹H-NMR (DMSO-d₆) δppm: 1.34 (6H, s), 6.25-6.40 (2H, m), 6.70 (1H, d, J=8.5 Hz), 9.09 (1H, s), 10.41 (1H, brs).

Reference Example 19 Synthesis of 6-hydroxy-2-methyl-4H-benzo[1,4]oxazin-3-one

The titled compound was obtained using 6-methoxy-2-methyl-4H-benzo[1,4]oxazin-3-one in the same manner as in Reference Example 18.

White Powder

¹H-NMR (DMSO-d₆) δppm: 1.34 (3H, d, J=6.8 Hz), 4.46 (1H, q, J=6.8 Hz), 6.23-6.27 (1H, m), 6.33 (1H, d, J=2.7 Hz), 6.70 (1H, d, J=8.6 Hz), 9.11 (1H, s), 10.44 (1H, brs).

Reference Example 20 Synthesis of 4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)piperidine

p-Toluenesulfonyl chloride (4.39 g, 23 mmol) was added to a pyridine solution (30 ml) of 4-(4-methoxyphenyl)piperidine (4.0 g, 21 mmol) and the mixture was stirred at room temperature overnight. Water was added to the solution mixture, which was then extracted with ethyl acetate. The organic phase was washed with hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated to dryness under reduced pressure to obtain 4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)piperidine (4.8 g) as white powder.

¹H-NMR (CDCl₃) δppm: 1.60-1.90 (4H, m), 2.30-2.40 (3H, m), 2.46 (3H, s), 3.78 (3H, s), 3.90-3.95 (2H, m), 6.84 (2H, dd, J=1.9, J=6.8 Hz), 7.07 (2H, dd, J=1.9, J=6.8 Hz), 7.35 (2H, d, J=8.2 Hz), 7.68 (2H, d, J=8.2 Hz).

Reference Example 21 Synthesis of 4-(4-hydroxyphenyl)-1-(toluene-4-sulfonyl)piperidine

The titled compound was obtained using 4-(4-methoxyphenyl)-1-(toluene-4-sulfonyl)piperidine in the same manner as in Reference Example 18.

Brown Powder

¹H-NMR (CDCl₃) δppm: 1.60-1.90 (4H, m), 2.30-2.50 (3H, m), 2.45 (3H, s), 3.90-3.95 (2H, m), 6.67 (1H, brs), 6.80 (2H, dd, J=1.9, J=6.8 Hz), 7.02 (2H, dd, J=1.8, J=6.9 Hz), 7.35 (2H, d, J=8.1 Hz), 7.68 (2H, d, J=8.1 Hz).

Reference Example 22 Synthesis of 4-bromo-2-hydroxymethyl-6-methoxyphenol

Sodium borohydride (0.28 g, 6.9 mmol) was added to a THF solution (30 ml) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.2 g 13.8 mmol) under ice cooling and the mixture was stirred at 0° C. for 2 hours. Acetic acid was added to the reaction solution to set pH at 3. 10% hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The extracted material was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1) and concentrated to dryness under reduced pressure to obtain 4-bromo-2-hydroxymethyl-6-methoxyphenol (3.23 g) as light yellow oil.

¹H-NMR (CDCl₃) δppm: 3.88 (3H, s), 4.71 (2H, s), 6.94 (1H, d, J=2.0 Hz), 7.03 (1H, d, J=2.0 Hz).

Reference Example 23 Synthesis of 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde

Ethyldiisopropylamine (3.01 ml, 17.1 mmol) and methoxymethylchloride (1.5 ml, 15.7 mmol) were added to a dichloromethane solution (30 ml) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.3 g, 14.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→11:9). The purified product was concentrated to dryness under reduced pressure to obtain 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde (4.2 g) as light yellow solid.

¹H-NMR (CDCl₃) δppm: 3.56 (3H, s), 3.89 (3H, s), 5.21 (2H, s), 7.23 (1H, d, J=2.5 Hz), 7.56 (1H, d, J=2.5 Hz), 10.39 (1H, s).

Reference Example 24 Synthesis of 3-methoxy-2-methoxymethoxy-5-(2-oxo-oxazolidin-3-yl)benzaldehyde

2-oxazolidinone (0.38 g, 4.36 mmol), dipalladium tris(dibenzylideneacetone) (0.17 g, 0.18 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (0.32 g, 0.55 mmol) and cesium carbonate (1.66 g, 5.1 mmol) were added to a dioxane solution (20 ml) of 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde (1.0 g, 3.6 mmol) and the mixture was stirred at 100° C. for 24 hours under an argon atmosphere. The reaction solution was cooled to room temperature and ethyl acetate was added thereto. The mixture was filtrated by cerite. The filtrate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the residue. The insoluble matter thus purified was obtained by filtration and dried to obtain 3-methoxy-2-methoxymethoxy-5-(2-oxo-oxazolidin-3-yl)benzaldehyde (0.5 g) as white powder.

¹H-NMR (CDCl₃) δppm: 3.57 (3H, s), 3.93 (3H, s), 4.06-4.12 (2H, m), 4.48-4.54 (2H, m), 5.21 (2H, s), 6.96 (1H, d, J=2.5 Hz), 8.18 (1H, d, J=2.5 Hz), 10.45 (1H, s).

Reference Example 25 Synthesis of 3-(3-methoxy-4-methoxymethoxy-5-methylphenyl)oxazolidin-2-one

3-Methoxy-2-methoxymethoxy-5-(2-oxo-oxazolidin-3-yl)benzaldehyde (0.5 g, 1.79 mmol) was dissolved in a solvent mixture of acetic acid (5 ml) and ethanol (5 ml) and 10% palladium carbon (0.05 g) was added thereto to perform catalytic reduction at 1 atm at 50° C. for 4 hours. The reaction mixture was cooled to room temperature and filtrated by cerite. The filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid (10 ml) and 10% palladium carbon (0.05 g) was added thereto to perform catalytic reduction at 1 atm at 50° C. for 6 hours. The solvent was removed under reduced pressure to obtain 3-(3-methoxy-4-methoxymethoxy-5-methylphenyl)oxazolidin-2-one as a crude product, which was subjected to the next reaction as it was.

¹H-NMR (CDCl₃) δppm: 2.32 (3H, s), 3.56 (3H, s), 3.85 (3H, s), 3.98-4.06 (2H, m), 4.43-4.50 (2H, m), 5.05 (2H, s), 6.61 (1H, d, J=2.3 Hz), 7.36 (1H, d, J=2.3 Hz).

Reference Example 26 Synthesis of 3-(4-hydroxy-3-methoxy-5-methylphenyl)oxazolidin-2-one

10% hydrochloric acid (5 ml) was added to a methanol solution (5 ml) of 3-(3-methoxy-4-methoxymethoxy-5-methylphenyl)oxazolidin-2-one (0.48 g, 1.79 mmol) and the mixture was stirred at 50° C. for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extracted material was dried over magnesium sulfate, and thereafter concentrated to dryness under reduced pressure to obtain 3-(4-hydroxy-3-methoxy-5-methylphenyl)oxazolidin-2-one (434 mg) as a light yellow powder.

¹H-NMR (CDCl₃) δppm: 2.26 (3H, s), 3.90 (3H, s), 4.02 (2H, dd, J=7.0 Hz, J=8.5 Hz), 4.46 (2H, dd, J=7.0 Hz, J=8.5 Hz), 5.55 (1H, br), 6.56 (1H, d, J=2.5 Hz), 7.31 (1H, d, J=2.5 Hz).

Reference Example 27 Synthesis of 1-(8-methoxy-2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)pyrrolidin-2-one

The titled compound was obtained using 6-bromo-8-methoxy-2,2-dimethyl-4H-benzo[1,3]dioxin and 2-pyrrolidone in the same manner as in Reference Example 25.

¹H-NMR (CDCl₃) δppm: 1.59 (6H, s), 2.09-2.21 (2H, m), 2.60 (2H, t, J=8.3 Hz), 3.82 (2H, t, J=7.0 Hz), 3.88 (3H, s), 4.83 (2H, s), 6.67 (1H, d, J=2.5 Hz), 7.24 (1H, d, J=2.5 Hz).

Reference Example 28 Synthesis of 1-(4-hydroxy-3-hydroxymethyl-5-methoxyphenyl)pyrrolidin-2-one

10% hydrochloric acid (4 ml) was added to a THF solution (7 ml) of 1-(8-methoxy-2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)pyrrolidin-2-one (0.36 g, 1.3 mmol) and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. The extracted material was dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol:=300:1→30:1). The purified product was concentrated to dryness under reduced pressure to obtain 1-(4-hydroxy-3-hydroxymethyl-5-methoxyphenyl)pyrrolidin-2-one (0.31 g) as light brown powder.

¹H-NMR (CDCl₃) δppm: 2.05-2.28 (3H, m), 2.26 (2H, t, J=7.5 Hz), 3.84 (2H, t, J=7.0 Hz), 3.91 (3H, s), 4.74 (2H, s), 5.90 (1H, br), 6.78 (1H, d, J=2.5 Hz), 7.52 (1H, d, J=2.5 Hz).

Reference Example 29 Synthesis of 3-methoxy-2-methoxymethoxy-5-(2-oxopyrrolidin-1-yl)benzaldehyde

The titled compound was obtained using 5-bromo-3-methoxy-2-methoxymethoxybenzaldehyde and 2-pyrrolidone in the same manner as Reference Example 25.

¹H-NMR (CDCl₃) δppm: 2.11-2.24 (2H, m), 2.63 (2H, t, J=8.3 Hz), 3.56 (3H, s), 3.89 (2H, t, J=7.0 Hz), 3.92 (3H, s), 5.21 (2H, s), 7.08 (1H, d, J=2.5 Hz), 8.28 (1H, d, J=2.5 Hz), 10.46 (1H, s).

Reference Example 30 Synthesis of 1-(4-hydroxy-3-methoxy-5-methylphenyl)pyrrolidin-2-one

3-methoxy-2-methoxymethoxy-5-(2-oxopyrrolidin-1-yl)benzaldehyde (0.72 g, 2.56 mmol) was dissolved in a solvent mixture of acetic acid (5 ml) and ethanol (7 ml) and 10% palladium carbon (70 mg) was added thereto to perform catalytic reduction at 50° C. for 10 hours. The reaction solution was cooled to room temperature and filtrated by cerite. The filtered cake was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane (15 ml) and trifluoroacetic acid (2.0 ml, 25.6 mmol) and triethylsilane (2.0 ml, 12.8 mmol) were added thereto under ice cooling. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→ethyl acetate). The purified product was concentrated under reduced pressure to obtain 1-(4-hydroxy-3-methoxy-5-methylphenyl)pyrrolidin-2-one (0.41 g) as light yellow oil.

¹H-NMR (CDCl₃) δppm: 2.17-2.25 (5H, m), 2.72 (2H, t, J=8.3 Hz), 3.88 (2H, t, J=7.0 Hz), 3.89 (3H, s), 6.66 (1H, d, J=2.5 Hz), 7.15 (1H, d, J=2.5 Hz).

Reference Example 31 Synthesis of 3,4-diacetoxy-5-methylbenzaldehyde

Acetic anhydride (1.2 ml, 12 mmol) was added to a pyridine solution (4 ml) of 3,4-dihydroxy-5-methylbenzaldehyde (0.72 g, 4.7 mmol) and the mixture was stirred at 0° C. for one hour. 10% hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→3:1). The purified product was concentrated under reduced pressure to obtain 3,4-diacetoxy-5-methylbenzaldehyde (0.98 g) as light yellow oil.

¹H-NMR (CDCl₃) δppm: 2.29 (3H, s), 2.32 (3H, s), 2.35 (3H, s), 7.58 (1H, d, J=1.6 Hz), 7.67 (1H, d, J=1.6 Hz), 9.93 (1H, s).

Reference Example 32 Synthesis of 7-hydroxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one

The titled compound was obtained using 7-methoxymethoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one in the same manner as in Reference Example 26.

White Powder

¹H-NMR (DMSO-d₆) δppm: 5.14 (2H, s), 6.35 (1H, d, J=2.2 Hz), 6.39 (1H, dd, J=8.1, J=2.2 Hz), 6.97 (1H, d, J=8.1 Hz), 9.98 (1H, br-s).

Reference Example 33 Synthesis of 7-methoxy-3,4-dihydro-1H-quinazolin-2-one

2-aminomethyl-5-methoxyaniline (1.2 g. 7.9 mmol) and carbonyl diimidazole (1.53 g, 9.5 mmol) were added to THF (100 ml) and the mixture was stirred at room temperature overnight. The insoluble matter precipitated was obtained by filtration, washed with dichloromethane and water, dried to obtain 7-methoxy-3,4-dihydro-1H-quinazolin-2-one (1.11 g) as white powder.

¹H-NMR (DMSO-d₆) δppm: 3.68 (3H, s), 4.23 (2H, s), 6.35 (1H, d, J=2.5 Hz), 6.42 (1H, dd, J=8.3 Hz, J=2.5 Hz), 6.96 (1H, d, J=8.3 Hz), 8.90 (1H, brs).

Reference Example 34 Synthesis of 7-hydroxy-3,4-dihydro-1H-quinazolin-2-one

The titled compound was obtained using 7-methoxy-3,4-dihydro-1H-quinazolin-2-one in the same manner as in Reference Example 18.

Light Brown Powder

¹H-NMR (DMSO-d₆) δppm: 4.18 (2H, brs), 6.75-6.85 (1H, m), 7.01 (1H, dd, J=2.0 Hz, J=9.0 Hz), 8.07 (1H, d, J=9.0 Hz), 8.87 (1H, brs), 9.48 (1H, brs), 13.21 (1H, brs).

Reference Example 35 Synthesis of methyl 5-(3-chloropropoxy)-1-methyl-1H-pyrazole-3-carboxylate

Cesium carbonate (2.08 g, 6.4 mmol) and 1-bromo-3-chloropropane (1.6 ml) were added to a DMF solution (5 ml) of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (0.83 g, 5.3 mmol) and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:1→4:1). The purified product was concentrated to dryness under reduced pressure to obtain methyl 5-(3-chloropropoxy)-1-methyl-1H-pyrazole-3-carboxylate (1.17 g) as white solid.

¹H-NMR (CDCl₃) δppm: 2.21-2.32 (2H, m), 3.72 (2H, t, J=6.3 Hz), 3.72 (2H, s), 3.91 (3H, s), 4.24 (2H, t, J=5.8 Hz), 6.10 (1H, s).

Reference Example 36 Synthesis of 7-(3-chloropropoxy)-2H-1,4-benzoxazin-3(4H)-one

The titled compound was obtained using 7-hydroxy-2H-1,4-benzoxazin-3(4H)-one and 1-bromo-3-chloropropane in the same manner as in Reference Example 35.

Light Brown Needle-Like Crystal (ethanol-n-hexane)

Melting point: 119-120° C.

The compounds listed in the following Tables 1 to 12 were produced using appropriate starting substances in the same manners as in Reference Examples 1 to 36.

TABLE 1

Reference Example R1 R2 R3 R4 R5 NMR 37 —H —H —CONHC₂H₅ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.25 (3H, t, J = 7.5 Hz), 2.29-2.39 (2H, m), 3.43-3.54 (2H, m), 3.61 (2H, t, J = 6.3 Hz), 4.15 (2H, t, J = 5.8 Hz), 5.99 (1H, br), 6.89-6.95 (2H, m), 7.70-7.75 (2H, m) 38 —H —H —CONHC₃H₇ —H —H ¹H-NMR (CDCl₃) δ ppm: 0.99 (3H, t, J = 7.5 Hz), 1.57-1.68 (2H, m), 2.23-2.36 (2H, m), 3.37-3.45 (2H, m), 3.61(2H, t, J = 6.3 Hz), 3.75 (2H, t, J = 6.3 Hz), 4.12-4.18 (2H, m), 6.02 (1H, br), 6.71-6.95 (2H, m), 7.71-7.75 (2H, m)

TABLE 2

Reference Example R1 R2 R3 R4 R5 NMR 39 —H —H —NO₂ —H —F ¹H-NMR (CDCl₃) δ ppm: 2.20-2.45 (2H, m), 3.70-3.80 (2H, m), 4.30-4.35 (2H, m), 7.07 (1H, dd, J = 8.2, 8.9 Hz), 8.00 (1H, dd, J = 2.7, 10.7 Hz), 8.07 (1H, dd, J = 0.9, 9.0 Hz). 40 —H —H —NH₂ —H —H ¹H-NMR (CDCl₃) δ ppm: 2.14-2.24 (2H, m ), 3.26 (2H, br), 3.73 (2H, t, J = 6.3 Hz), 4.04 (2H, t, J = 5.8 Hz), 6.61-5.67 (2H, m), 6.72-6.78 (2H, m) 41 —H —H —NHCO₂CH₃ —H —H ¹H-NMR (CDCl₃) δ ppm: 2.15-2.25 (2H, m), 3.74 (2H, t, J = 6.3 Hz), 3.76 (3H, s), 4.09 (2H, t, J = 5.8 Hz), 6.42 (1H, br), 6.85 (2H, dd, J = 2.5, 6.8 Hz), 7.21-7.33 (2H, m) 42 —H —H —CH₂CON(C₂H₅)₂ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.07-1.14 (6H, m), 2.17-2.30 (2H, m), 3.26-3.42 (4H, m), 3.63 (2H, s), 3.74 (2H, t, J = 6.3 Hz), 4.09 (2H, t, J = 5.8 Hz), 6.83-6.88 (2H, m), 7.14-7.19 (2H, m) 43 —H —H —H —NHCO₂CH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.28-2.37 (2H, m ), 3.74 (2H, t, J = 6.5 Hz), 3.77 (3H, s), 4.11 (2H, t, J = 6.0 Hz), 6.50-6.67 (2H, m ), 6.83 (1H, dd, J = 1.5 Hz, 7.8 Hz), 7.16-7.22 (2H, m) 44 —H —H —NHSO₂C₂H₅ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.37 (3H, t, J = 7.4 Hz), 2.15-2.30 (2H, m), 3.07 (2H, q, J = 7.4 Hz), 3.75 (2H, t, J = 6.3 Hz), 4.10 (2H, t, J = 5.8 Hz), 6.41 (1H, brs), 6.88 (2H, dt, J = 8.9, 3.4 Hz), 7.19 (2H, dt, J = 8.9, 3.4 Hz). 45 —H —H —NH₂ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.15-2.30 (2H, m), 3.20-3.70 (2H, br), 3.75-3.95 (2H, m), 3.83 (3H, s), 4.07 (2H, t, J = 3 Hz), 6.24 (1H, dd, J = 2.6, 8.4 Hz), 6.33 (1H, d, J = 2.7 Hz), 6.77 (1H, d, J = 8.4 Hz). 46 —H —H —NHCO₂CH₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.20-2.30 (2H, m), 3.77 (3H, s), 3.86 (3H, s), 4.13 (2H, t, J = 6.0 Hz), 6.55 (1H, brs), 6.73 (1H, dd, J = 2.4, 8.6 Hz), 6.84 (1H, d, J = 8.6 Hz), 7.20 (1H, brs). 47 —H —H —CONHC₂H₅ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.23 (3H, t, J = 7.3 Hz), 2.20-2.30 (2H, m), 3.40-3.50 (2H, m), 3.74 (2H, t, J = 6.3 Hz), 4.14 (2H, t, J = 5.8 Hz), 6.13 (1H, brs), 6.85-6.95 (2H, m), 7.70-7.75 (2H, m). 48 —H —H —NHCON(CH₃)₂ —H —H ¹H-NMR (CDCl₃) δ ppm: 2.15-2.25 (2H, m), 3.02 (6H, s), 3.74 (2H, t, J = 6.4 Hz), 4.08 (2H, t, J = 5.9 Hz), 6.20 (1H, brs), 6.84 (2H, dd, J = 2.0, 6.8 Hz), 7.26 (2H, dd, J = 2.1, 6.8 Hz). 49 —H —H —CO₂C₂H₅ —H —Cl ¹H-NMR (CDCl₃) δ ppm: 1.39 (3H, t, J = 7.0 Hz), 2.27-2.37 (2H, m), 3.81 (2H, t, J = 6.8 Hz), 4.25 (2H, t, J = 6.3 Hz), 4.36 (2H, q, J = 7.0 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.93 (1H, dd, J = 2.0 Hz, 8.5 Hz), 8.06 (1H, d, J = 2.0 Hz)

TABLE 3

Reference Example R1 R2 R3 R4 R5 NMR 50 —H —H —CH₂CO₂C₂H₅ —H —Cl ¹H-NMR (CDCl₃) δ ppm: 1.26 (3H, t, J = 7.0 Hz), 2.23-2.33 (2H, m), 3.52 (2H, s), 3.80 (2H, t, J = 6.3 Hz), 4.15 (2H, q, J = 7.0 Hz), 6.90 (1H, d, J = 8.3 Hz), 7.13 (1H, dd, J = 2.0 Hz, 8.3 Hz), 7.30 (1H, d, J = 2.0 Hz) 51 —H —H —CH₂CONHCH₃ —H —H ¹H-NMR (CDCl₃) δ ppm: 2.19-2.29 (2H, m ), 2.76 (3H, d, J = 4.8 Hz), 3.52 (2H, s), 3.76 (2H, t, J = 6.3 Hz), 4.12 (2H, t, J = 5.8 Hz), 5.35 (1H, br), 6.86-6.92 (2H, m), 7.13-7.18 (2H, m) 52 —H —H —CH₂CH₂NHCH₃ —H —H ¹H-NMR (CDCl₃) δ ppm: 2.18-2.27 (2H, m ), 2.43 (2H, s), 2.72-2.83 (4H, m), 3.71 (3H, s), 3.75 (4H, t, J = 6.3 Hz), 4.09 (2H, t, J = 5.8 Hz), 6.83-6.86 (2H, m), 7.10-7.14 (2H, m) 53 —H —H —(CH₂)₂N(CH₃)CO₂C(CH₃)₃ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.42 (9H, s), 2.17-2.27 (2H, m), 2.67-2.86 (5H, m), 3.35-3.41 (2H, m), 3.74 (2H, t, J = 6.3 Hz), 4.09 (2H, t, J = 5.8 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.00-7.16 (2H, m) 54 —H —H —NH₂ —H —F ¹H-NMR (CDCl₃) δ ppm: 2.15-2.25 (2H, m), 3.54 (2H, brs), 3.76 (2H, t, J = 6.4 Hz), 4.05-4.15 (2H, m), 6.35-6.40 (1H, m), 6.46 (1H, dd, J = 0.9, 12.6 Hz), 6.82 (1H, dd, J = 8.5, 8.5 Hz). 55 —H —H —NHCO₂CH₃ —H —F ¹H-NMR (CDCl₃) δ ppm: 2.20-2.30 (2H, m), 3.77 (2H, t, J = 6.5 Hz), 3.77 (3H, s), 4.10-4.20 (2H, m), 6.57 (1H, brs), 6.85-7.00 (2H, m), 7.25-7.30 (1H, m). 56 —H —H —CH₂CO₂C₂H₅ —H —F ¹H-NMR (CDCl₃) δ ppm: 1.26(3H, t, J = 7.0 Hz), 2.21-2.30 (2H, m), 3.5382H, s), 3.77 (2H, t, J = 6.3 Hz), 4.11-4.20 (4H, m), 6.89-7.06 (3H, m) 57 —H —H —CO₂C₂H₅ —H —Br ¹H-NMR (CDCl₃) δ ppm: 1.39 (3H, t, J = 7.0 Hz), 2.27-2.37 (2H, m), 3.82 (2H, t, J = 6.3 Hz), 4.24 (2H, t, J = 5.8 Hz), 4.35 (2H, q, J = 7.0 Hz), 6.92 (1H, d, J = 8.5 Hz), 7.98 (1H, dd, J = 2.0 Hz, 8.5 Hz), 8.23 (1H, d, J = 2.0 Hz) 58 —H —H —CHO —OCH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.23-2.34 (2H, m ), 3.76 (2H, t, J = 6.3 Hz), 3.91 (3H, s), 4.20 (2H, t, J = 5.8 Hz), 6.46 (1H, d, J = 2.0 Hz), 6.56 (1H, dd, J = 2.0 Hz, 8.3 Hz), 7.81(1H, d, J = 8.3 Hz), 10.29 (1H, s) 59 —H —H —CO₂C₂H₅ —H —NO₂ ¹H-NMR (CDCl₃) δ ppm: 1.41 (3H, t, J = 7.0 Hz), 2.26-2.40 (2H, m), 3.81 (2H, t, J = 6.3 Hz), 4.32-4.44 (4H, m), 7.15 (1H, d, J = 8.8 Hz), 8.22 (1H, dd, J = 2.0 Hz, 8.8 Hz), 8.52 (1H, d, J = 2.0 Hz)

TABLE 4

Reference Example R1 R2 R3 R4 R5 NMR 60 —H —H —CONHC₂H₅ —H —NO₂ ¹H-NMR (CDCl₃) δ ppm: 1.26 (3H, t, J = 7.3 Hz), 2.25-2.35 (2H, m), 3.45-3.55 (2H, m), 3.80 (2H, t, J = 6.1 Hz), 4.30-4.35 (2H, m), 6.34 (1H, brs), 7.15 (1H, d, J = 8.8 Hz), 8.04 (1H, dd, J = 2.3, 8.8 Hz), 8.25 (1H, d, J = 2.3 Hz). 61 —H —H —CONH₂ —OCH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.21-2.35 (2H, m), 3.75 (2H, t, J = 6.3 Hz), 3.95 (3H, s), 4.18 (2H, t, J = 5.8 Hz), 5.67 (1H, br), 6.51(1H, d, J = 2.5 Hz), 6.61 (1H, dd, J = 2.5 Hz, 8.8 Hz), 7.59 (1H, br), 8.18 (1H, d, J = 8.8 Hz ) 62 —H —H —CONHCH₃ —OCH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.20-2.30 (2H, m ), 2.99 (3H, d, J = 5.0 Hz), 3.75 (2H, t, J = 6.3 Hz), 3.94 (3H, s), 4.17 (2H, t, J = 6.0 Hz), 6.49 (1H, d, J = 2.5 Hz), 6.60 (1H, dd, J = 2.5 Hz, 8.8 Hz), 7.70 (1H, br), 8.19 (1H, d, J = 8.8 Hz) 63 —H —H —CONHC₂H₅ —OCH₃ —H ¹H-NMR (CDCl₃) δ ppm: 1.23 (3H, t, J = 7.3 Hz), 2.20-2.30 (2H, m), 3.43-3.54 (2H, m), 3.75 (2H, t, J = 6.3 Hz), 3.94 (3H, s), 4.17 (2H, t, J = 6.3 Hz), 6.49 (1H, d, J = 2.5 Hz), 6.60 (1H, dd, J = 2.5 Hz, 8.8 Hz), 7.70 (1H, br ), 8.18 (1H, d, J = 8.8 Hz ) 64 —H —H —CONHCH₂CF₃ —OCH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.21-2.31 (2H, m ), 3.75 (2H, t, J = 6.3 Hz), 3.98 (3H, s), 4.07-4.21(4H, m), 6.51 (1H, d, J = 2.5 Hz), 6.62 (1H, dd, J = 2.5 Hz, 8.8 Hz), 8.09 (1H, br), 8.18 (1H, d, J = 8.8 Hz ) 65 —H —H —CH═CHCO₂C₂H₅ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.33 (3H, t, J = 7.0 Hz), 2.20-2.30 (2H, m), 3.75 (2H, t, J = 6.3 Hz), 4.15 (2H, t, J = 5.8 Hz), 4.25 (2H, q, J = 7.0 Hz), 6.31 (1H, d, J = 16.0 Hz), 6.88-6.93 (2H, m), 7.44-7.50 (2H, m), 7.64 (1H, d, J = 16.0 Hz) 66 —F —H —H —CO₂C₂H₅ —H ¹H-NMR (CDCl₃) δ ppm: 1.40 (3H, t, J = 7.0 Hz), 2.25-2.34 (2H, m), 3.78 (2H, t, J = 6.3 Hz), 4.25 (2H, t, J = 5.8 Hz), 4.37 (2H, q, J = 7.0 Hz), 7.08-7.15 (1H, m), 7.62-7.70 (2H, m) 67 —H —H —CO₂H —CH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.21-2.31 (2H, m ), 2.64 (3H, s), 3.75 (2H, t, J = 6.3 Hz), 4.18 (2H, t, J = 5.8 Hz), 6.77-6.81 (2H, m), 8.06 (1H, d, J = 9.5 Hz), 11.00 (1H, br) 68 —Cl —H —H —CO₂C₂H₅ —H ¹H-NMR (CDCl₃) δ ppm: 1.40 (3H, t, J = 7.0 Hz), 2.25-2.37 (2H, m), 3.82 (2H, t, J = 6.3 Hz), 4.25 (2H, t, J = 5.8 Hz), 4.38 (2H, q, J = 7.0 Hz), 7.42 (1H, d, J = 8.5 Hz), 7.58-7.62 (2H, m) 69 —CH₃ —H —H —CO₂C₂H₅ —H ¹H-NMR (CDCl₃) δ ppm: 1.39 (3H, t, J = 7.0 Hz), 2.24-2.34 (2H, m), 2.26 (3H, s), 3.78 (2H, t, J = 6.3 Hz), 4.19 (2H, t, J = 5.8 Hz), 4.37 (2H, q, J = 7.0 Hz), 7.19 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 1.5 Hz), 7.57 (1H, dd, J = 1.5 Hz, 7.8 Hz)

TABLE 5

Reference Example R1 R2 R3 R4 R5 NMR 70 —H —H —CONH₂ —CH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.19-2.29 (2H, m), 2.51 (3H, s), 3.75 (2H, t, J = 6.3 Hz), 4.14 (2H, t, J = 6.3 Hz), 6.53 (2H, br), 6.71 (2H, m), 7.45 (1H, d, J = 8.3 Hz) 71 —H —H —CONHCH₃ —CH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.18-2.28 (2H, m), 2.45 (3H, s), 2.98 (3H, d, J = 4.9 Hz), 3.74 (2H, t, J = 6.3 Hz), 4.12 (2H, t, J = 5.8 Hz), 5.72 (1H, br), 6.68-6.75 (2H, m), 7.32 (1H, d, J = 8.3 Hz) 72 —H —H —CONHC₂H₅ —CH₃ —H ¹H-NMR (CDCl₃) δ ppm: 1.24 (3H, t, J = 7.3 Hz), 2.19-2.28 (2H, m), 2.45 (3H, s), 3.41-3.52 (2H, m), 3.74 (2H, t, J = 6.3 Hz), 4.12 (2H, t, J = 6.0 Hz), 5.68 (1H, br), 6.68-6.75 (2H, m), 7.32 (1H, d, J = 8.3 Hz) 73 —CH₃ —H —CO₂C₂H₅ —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.38 (3H, t, J = 7.0 Hz), 2.21-2.28 (2H, m), 2.31 (6H, s), 3.84 (2H, t, J = 6.3 Hz), 3.93 (2H, t, J = 5.8 Hz), 4.35 (2H, t, J = 7.0 Hz), 7.72 (2H, s) 74 —H —CO₂C₂H₅ —H —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 1.39 (3H, t, J = 7.1 Hz), 2.26-2.36 (2H, m), 3.78 (2H, t, J = 6.3 Hz), 3.91 (3H, s), 4.22 (2H, t, J = 5.8 Hz), 4.36 (2H, q, J = 7.1 Hz), 6.89 (1H, d, J = 8.3 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.70 (1H, d, J = 8.3 Hz) 75 —OCH₃ —H —CO₂C₂H₅ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 1.40 (3H, t, J = 7.0 Hz), 2.13-2.23 (2H, m), 3.85 (2H, t, J = 6.3 Hz), 3.90 (6H, s), 4.17 (2H, t, J = 5.8 Hz), 4.38 (2H, q, J = 7.0 Hz), 7.30 (2H, s) 76 —CH₃ —H —CHO —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.17-2.29 (2H, m), 2.34 (3H, s), 3.83 (2H, t, J = 6.3 Hz), 3.91 (3H, s), 4.18 (2H, t, J = 5.8 Hz), 7.31 (1H, s), 9.86 (1H, s) 77 —CH₃ —H —CO₂H —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.18-2.28 (2H, m), 2.32 (6H, s), 3.83 (2H, t, J = 6.3 Hz), 3.90 (3H, s), 4.16 (2H, t, J = 5.8 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.60 (1H, d, J = 2.0 Hz) 78 —CH₃ —H —CONH₂ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.17-2.27 (2H, m), 2.30 (3H, s), 3.83 (2H, t, J = 6.3 Hz), 3.89 (3H, s), 4.12 (2H, t, J = 5.8 Hz), 5.24-6.26 (2H, br), 7.15 (1H, d, J = 2.0 Hz), 7.32 (1H, d, J = 2.0 Hz) 79 —CH₃ —H —CONHCH₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.17-2.26 (2H, m), 2.29 (3H, s), 3.00 (3H, d, J = 5.0 Hz), 3.83 (2H, t, J = 6.3 Hz), 3.88 (3H, s), 4.10 (2H, t, J = 5.8 Hz), 6.06 (1H, br), 7.08 (1H, d, J = 1.9 Hz), 7.28 (1H, d, J = 1.9 Hz)

TABLE 6

Reference Example R1 R2 R3 R4 R5 NMR 80 —CH₃ —H —CONHC₂H₅ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 1.25 (3H, t, J = 7.3 Hz), 2.17-2.26 (2H, m), 2.30 (3H, s), 3.43-3.54 (2H, m), 3.83 (2H, t, J = 6.3 Hz), 3.89 (3H, s), 4.10 (2H, t, J = 5.8 Hz), 6.02 (1H, br), 7.07 (1H, d, J = 2.0 Hz), 7.28 (1H, d, J = 2.0 Hz) 81 —CH₃ —H —NHCO₂C(CH₃)₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 1.51 (9H, s), 2.14-2.26 (2H, m), 2.23 (3H, s), 3.82 (2H, t, J = 6.3 Hz), 3.83 (3H, s), 3.99 (2H, t, J = 5.8 Hz), 6.34 (1H, br), 6.59 (1H, d, J = 2.5 Hz), 7.01 (1H, d, J = 2.5 Hz) 82 —CH₃ —H —NHCO₂CH₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.17-2.29 (2H, m), 2.30 (3H, s), 3.83 (2H, t, J = 6.3 Hz), 3.89 (6H, s), 4.13 (2H, t, J = 5.8 Hz), 7.44 (1H, d, J = 2.0 Hz), 7.51 (1H, d, J = 2.0 Hz) 83 —CH₃ —H —CO₂CH₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.15-2.30 (2H, m), 2.29 (3H, s), 3.75-3.90 (2H, m), 3.88 (3H, s), 3.89 (3H, s), 4.13 (2H, t, J = 5.9 Hz), 7.43 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 1.4 Hz). 84 —CH₃ —H —NH₂ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.14-2.22 (2H, m), 2.19 (3H, s), 3.47 (2H, br), 3.82 (2H, t, J = 5.3 Hz), 3.95 (2H, t, J = 4.8 Hz), 6.09-6.13 (2H, m) 85 —CH₃ —H —NHCOCH₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.11-2.28 (2H, m), 2.15 (3H, s), 2.24 (3H, s), 3.82 (2H, t, J = 6.3 Hz), 3.83 (3H, s), 4.01 (2H, t, J = 5.8 Hz), 6.66 (1H, d, J = 2.1 Hz), 7.02 (1H, br), 7.23 (1H, d, J = 2.1 Hz) 86 —CH₃ —H —CHO —H —OCOCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.17-2.27 (2H, m), 2.37 (6H, s), 3.79 (2H, t, J = 5.6 Hz), 4.11 (2H, t, J = 5.8 Hz), 7.46 (1H, d, J = 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 9.88 (1H, s) 87 —CH₃ —H —CO₂H —H —OCOCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.16-2.26 (2H, m), 2.35 (3H, s), 2.36 (3H, s), 3.79 (2H, t, J = 6.3 Hz), 4.09 (2H, t, J = 5.8 Hz), 7.67 (1H, d, J = 2.0 Hz), 7.84 (1H, d, J = 2.0 Hz) 88 —OH —H —CONHCH₃ —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 2.21-2.35 (2H, m), 2.32 (3H, s), 2.99 (3H, d, J = 4.9 Hz), 3.85 (2H, t, J = 6.3 Hz), 4.05 (2H, t, J = 5.8 Hz), 5.90 (1H, br), 6.02 (1H, br), 7.15 (1H, d, J = 1.8 Hz), 7.20 (1H, d, J = 2.0 Hz) 89 —CH₃ —H —CONHCH₃ —H —OC₂H₅ ¹H-NMR (CDCl₃) δ ppm: 1.46 (3H, t, J = 7.0 Hz), 2.17-2.27 (2H, m), 2.28 (3H, s), 2.99 (3H, d, J = 5.0 Hz), 3.83 (2H, t, J = 6.3 Hz), 4.06-4.15 (4H, m), 6.04 (1H, br), 7.07 (1H, d, J = 1.8 Hz), 7.25 (1H, d, J = 1.8 Hz) 90 —H —H —CO₂H —OCH₃ —H ¹H-NMR (CDCl₃) δ ppm: 2.22-2.32 (2H, m), 3.75 (2H, t, J = 6.3 Hz), 4.05 (3H, s), 4.21 (2H, t, J = 5.8 Hz), 6.55 (1H, d, J = 2.5 Hz), 6.66 (1H, d, J = 8.8 Hz), 8.14 (1H, d, J = 8.8 Hz), 10.43 (1H, br)

TABLE 7

Reference Example R1 R2 R3 R4 R5 NMR 91 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 2.2-2.3 (2H, m), 3.77 (2H, t, J = 6.3 Hz), 4.16 (2H, t, J = 5.8 Hz), 7.00 (2H, dd, J = 2.2, 6.7 Hz), 7.15-7.25 (2H, m), 7.25-7.35 (2H, m), 7.76 (1H, s). 92 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 2.26 (2H, t, J = 6.1 Hz), 3.75 (2H, t, J = 6.3 Hz), 4.15 (2H, t, J = 5.7 Hz), 7.00 (1H, dd, J = 2.1, 6.9 Hz), 7.56 (1H, dd, J = 2.2, 7.1 Hz), 8.07 (1H, s), 8.45 (1H, s). 93 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 1.70-1.90 (4H, m), 2.10-2.40 (3H, m), 2.45 (3H, s), 3.55-3.75 (2H, m), 3.90-3.95 (2H, m), 4.05-4.15 (2H, m), 6.84 (2H, dd, J = 1.9, 6.8 Hz), 7.06 (2H, dd, J = 1.8, 6.9 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.68 (2H, d, J = 8.2 Hz). 94 —CH₃ —H

—H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.16-2.25 (2H, m), 2.28 (3H, s), 3.83 (2H, t, J = 6.3 Hz), 3.86 (3H, s), 3.99-4.06 (4H, m), 4.46 (2H, dd, J = 6.3 Hz, 8.8 Hz), 6.61 (1H, d, J = 2.5 Hz), 7.33 (1H, d, J = 2.5 Hz) 95 —OCH₃ —H

—H —CH₂OH ¹H-NMR (CDCl₃) δ ppm: 2.09-2.28 (2H, m), 2.61 (2H, t, J = 7.8 Hz), 3.79-3.87 (4H, m), 3.88 (3H, s), 4.13 (2H, t, J = 5.5 Hz), 4.71 (2H, d, J = 5.8 Hz), 6.85 (1H, d, J = 2.5 Hz), 7.59 (1H, d, J = 2.5 Hz) 96 —CH₃ —H

—H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 2.05-2.25 (4H, m), 2.27 (3H, s), 2.60 (2H, t, J = 8.3 Hz), 3.79-3.89 (42H, m), 3.86 (3H, s), 6.71 (1H, d, J = 2.5 Hz), 7.37 (1H, d, J = 2.5 Hz)

TABLE 8

Reference Example R1 R2 R3 R4 R5 NMR 97 —H —H —H —NO₂ —H ¹H-NMR (CDCl₃) δ ppm: 1.93-2.11 (4H, m), 3.59-3.70 (2H, m), 4.00-4.13 (2H, m), 7.20-7.24 (1H, m), 7.43 (1H, t, J = 8.0 Hz), 7.72 (1H, t, J = 2.3 Hz), 7.80-7.84 (1H, m) 98 —H —H —H —CN —H ¹H-NMR (CDCl₃) δ ppm: 1.96-2.00 (4H, m), 3.60-3.65 (2H, m), 3.99-4.14 (2H, m), 7.10-7.14 (2H, m), 7.22-7.26 (1H, m), 7.34-7.40 (1H, m)

TABLE 9 R1—O—(CH2)3—Cl Reference Example R1 NMR  99

¹H-NMR (CDCl₃) δ ppm: 2.15-2.30 (2H, m), 3.72 (2H, t, J = 6.3 Hz), 3.87 (3H, s), 4.05-4.15 (2H, m), 6.55 (1H, d, J = 1.8 Hz), 7.42 (1H, d, J = 1.8 Hz). 100

¹H-NMR (CDCl₃) δ ppm: 2.21-2.31 (2H, m), 3.70 (2H, t, J = 6.3 Hz), 3.95 (3H, s), 4.46 (2H, t, J = 6.0 Hz), 6.54 (1H, s) 101

¹H-NMR (CDCl₃) δ ppm: 2.21-2.32 (2H, m), 3.72 (2H, t, J = 6.3 Hz), 3.72 (2H, s), 3.91 (3H, s), 4.24 (2H, t, J = 5.8 Hz), 6.10 (1H, s) 102

¹H-NMR (CDCl₃) δ ppm: 1.39 (3H, t, J = 7.0 Hz), 1.39 (3H, t, J = 7.3 Hz), 2.22-2.32 (2H, m), 3.71 (2H, t, J = 6.3 Hz), 4.10 (2H, q, J = 7.3 Hz), 4.24 (2H, t, J = 5.8 Hz), 4.39 (2H, q, J = 7.0 Hz), 6.08 (1H, s) 103

¹H-NMR (CDCl₃) δ ppm: 2.20-2.29 (2H, m), 2.46 (3H, s), 3.72 (2H, t, J = 6.3 Hz), 4.12 (2H, t, J = 5.8 Hz), 6.84 (1H, dd, J = 2.5 Hz, 8.8 Hz), 7.13 (1H, d, J = 8.8 Hz), 8.07 (1H, d, J = 2.5 Hz) 104

¹H-NMR (CDCl₃) δ ppm: 2.13 (3H, s), 2.21-2.31 (2H, m), 3.76 (2H, t, J = 6.3 Hz), 4.18 (2H, t, J = 5.8 Hz), 5.17 (2H, s), 7.19-7.32 (2H, m), 8.30 (1H, d, J = 2.5 Hz) 105

¹H-NMR (CDCl₃) δ ppm: 2.27-2.36 (2H, m), 3.77 (2H, t, J = 6.0 Hz), 4.28 (2H, t, J = 5.8 Hz), 7.33 (1H, dd, J = 2.5 Hz, 8.5 Hz), 7.97 (1H, dd, J = 2.5 Hz, 8.5 Hz), 8.44 (1H, d, J = 2.5 Hz), 10.00 (1H, s) 106

¹H-NMR (CDCl₃) δ ppm: 1.26 (3H, t, J = 7.3 Hz), 2.24-2.34 (2H, m), 3.55 (2H, dq, J = 6.0 Hz, 7.3 Hz), 3.77 (2H, t, J = 6.3 Hz), 4.22 (2H, t, J = 5.8 Hz), 7.29 (1H, dd, J = 2.3 Hz, 8.8 Hz), 7.83 (1H, br), 8.18 (1H, d, J = 8.8 Hz), 8.20 (1H, d, J = 2.3 Hz) 107

¹H-NMR (CDCl₃) δ ppm: 2.25-2.34 (2H, m), 3.77 (2H, t, J = 6.3 Hz), 4.23 (2H, t, J = 5.8 Hz), 5.48 (1H, br), 7.31 (1H, dd, J = 2.3 Hz, 8.8 Hz), 7.68 (1H, br), 8.16 (1H, d, J = 8.8 Hz), 8.23 (1H, d, J = 2.3 Hz) 108

¹H-NMR (CDCl₃) δ ppm: 2.24-2.34 (2H, m), 3.73 (2H, t, J = 6.3 Hz), 4.00 (3H, s), 4.58 (2H, t, J = 6.0 Hz), 8.28 (1H, d, J = 1.3 Hz), 8.87 (1H, d, J = 1.3 Hz)

TABLE 10 R1—O—(CH2)3—Cl Reference Example R1 NMR 109

¹H-NMR (CDCl₃) δ ppm: 1.44 (3H, t, J = 7.0 Hz), 2.22-2.31 (2H, m), 3.72 (2H, t, J = 6.3 Hz), 4.48 (2H, q, J = 7.0 Hz), 4.59 (2H, t, J = 6.0 Hz), 7.44 (1H, d, J = 1.0 Hz), 8.90 (1H, d, J = 1.0 Hz) 110

¹H-NMR (CDCl₃) δ ppm: 2.20-2.30 (2H, m), 2.70-2.75 (2H, m), 3.07 (2H, t, J = 5.8 Hz), 3.74 (2H, t, J = 6.4 Hz), 7.15-7.20 (2H, m), 7.37 (1H, d, J = 8.2 Hz). 111

¹H-NMR (DMSO- d₆) δ ppm: 2.1-2.2 (2H, m), 3.37 (2H, s), 3.78 (2H, t, J = 6.5 Hz), 4.04 (2H, t, J = 6 Hz), 6.40 (1H, d, J = 2.5 Hz), 6.49 (1H, dd, J = 2.5, 8 Hz), 7.08 (1H, d, J = 8 Hz), 10.33 (1H, bs). 112

¹H-NMR (CDCl₃) δ ppm: 2.27 (2H, t, J = 6.1 Hz), 3.76 (2H, t, J = 6.3 Hz), 4.19 (2H, t, J = 5.7 Hz), 4.41 (2H, s), 6.96 (1H, s), 7.01 (1H, dd, J = 2.2, 8.5 Hz), 7.17 (1H, brs), 7.77 (1H, d, J = 8.4 Hz). 113

¹H-NMR (CDCl₃) δ ppm: 2.27 (2H, t, J = 6.1 Hz), 3.76 (2H, t, J = 6.3 Hz), 4.19 (2H, t, J = 5.7 Hz), 4.40 (2H, s), 6.50-6.60 (1H, br), 7.15 (1H, dd, J = 2.3, 8.5 Hz), 7.35- 7.40 (2H, m). 114

¹H-NMR (CDCl₃) δ ppm: 2.20-2.35 (2H, m), 3.39 (3H, s), 3.75-3.80 (2H, m), 4.05-4.15 (2H, m), 6.55-6.65 (2H, m), 6.98 (1H, d, J = 7.5 Hz), 9.92 (1H, brs). 115

¹H-NMR (CDCl₃) δ ppm: 2.28 (2H, t, J = 6.0 Hz), 3.75-3.80 (5H, m), 4.18 (2H, t, J = 5.7 Hz), 6.85 (1H, d, J = 2.1 Hz), 6.90-6.95 (1H, m), 7.66 (1H, d, J = 8.8 Hz), 7.76 (1H, s). 116

¹H-NMR (CDCl₃) δ ppm: 2.20-2.30 (2H, m), 3.78 (2H, t, J = 6.9 Hz), 3.82 (3H, s), 4.18 (2H, t, J = 5.8 Hz), 6.97 (1H, dd, J = 2.3, 8.8 Hz), 7.25-7.30 (2H, m), 7.81 (1H, s). 117

¹H-NMR (CDCl₃) δ ppm: 2.20-2.35 (2H, m), 3.77 (2H, t, J = 6.2 Hz), 4.19 (2H, t, J = 6.0 Hz), 4.66 (2H, s), 6.47 (1H, dd, J = 7.9, 1.2 Hz), 6.67 (1H, dd, J = 8.3, 1.1 Hz), 6.90 (1H, dd, J = 8.2, 8.1 Hz), 8.29 (1H, brs). 118

¹H-NMR (CDCl₃) δ ppm: 2.24 (2H, tt, J = 6.2, 6.2 Hz), 3.70 (2H, t, J = 6.4 Hz), 3.77 (3H, s), 4.45 (2H, t, J = 6.1 Hz), 6.70 (1H, d, J = 8.9 Hz), 6.98 (1H, dd, J = 8.9, 3.0 Hz), 7.35 (1H, d, J = 3.0 Hz)

TABLE 11 R1—O—(CH2)3—Cl Reference Example R1 NMR 119

¹H-NMR (CDCl₃) δ ppm: 2.30 (2H, tt, J = 6.1, 6.1 Hz), 3.60 (3H, s), 3.77 (2H, t, J = 6.3 Hz), 4.25 (2H, t, J = 5.8 Hz), 7.34 (1H, dd, J = 8.9, 2.9 Hz), 7.65 (1H, d, J = 8.9 Hz), 7.68 (1H, d, J = 2.9 Hz), 7.96 (1H, s) 120

¹H-NMR (CDCl₃) δ ppm: 2.12 (2H, tt, J = 6.3, 6.3 Hz), 2.24 (2H, tt, J = 6.1, 6.1 Hz), 2.62 (2H, t, J = 6.5 Hz), 2.902 (2H, t, J = 6.1 Hz), 3.74 (2H, t, J = 6.3 Hz), 4.15 (2H, t, J = 5.8 Hz), 7.05 (1H, dd, J = 8.4, 2.8 Hz), 7.17 (1H, d, J = 8.4 Hz), 7.52 (1H, d, J = 2.8 Hz) 121

¹H-NMR (CDCl₃) δ ppm: 2.25 (2H, tt, J = 6.1, 6.1 Hz), 3.76 (3H, s), 3.78 (2H, t, J = 6.4 Hz), 4.15 (2H, t, J = 5.8 Hz), 6.39 (1H, t, J = 3.0 Hz), 6.88 (1H, dd, J = 8.8, 2.4 Hz), 7.02 (1H, d, J = 3.0 Hz), 7.10 (1H, d, J = 2.3 Hz), 7.21 (1H, d, J = 8.8 Hz)

TABLE 12 R1—O—(CH2)3—Cl Reference Example R1 NMR 122

¹H-NMR (CDCl₃) δ ppm: 1.85-2.05 (4H, m), 3.62 (2H, t, J = 6.3 Hz), 4.33 (2H, t, J = 6.3 Hz), 6.72 (1H, d, J = 8.3 Hz), 6.85 (1H, dt, J = 0.8, 5.1 Hz), 7.56 (1H, dt, J = 2.0, 8.4 Hz), 8.14 (1H, dd, J = 5.1, 1.4 Hz). 123

¹H-NMR (CDCl₃) δ ppm: 1.95-2.05 (4H, m), 3.62 (2H, t, J = 6.2 Hz), 4.05 (2H, t, J = 5.8 Hz), 6.80 (2H, dd, J = 4.8, 1.6 Hz), 8.43 (2H, dd, J = 4.9, 1.5 Hz). 124

¹H-NMR (DMSO- d₆) δ ppm: 1.75-1.9 (4H, m), 3.36 (2H, s), 3.70 (2H, t, J = 6.5 Hz), 3.96 (2H, t, J = 6 Hz), 6.38 (1H, d, J = 2 Hz), 6.48 (1H, dd, J = 2.5, 8 Hz), 7.07 (1H, d, J = 8 Hz), 10.32 (1H, bs). 125

¹H-NMR (CDCl₃) δ ppm: 1.91-2.00 (4H, m), 3.62 (2H, t, J = 6.2 Hz), 3.98 (2H, t, J = 5.6 Hz), 5.26 (2H, s), 6.36 (1H, d, J = 2.3 Hz), 6.57 (1H, dd, J =, 8.4, 2.3 Hz), 7.00 (1H, d, J = 8.4 Hz), 8.08 (1H, br-s) 126

¹H-NMR (CDCl₃) δ ppm: 1.95-2.04 (4H, m), 3.61-3.65 (2H, m), 4.06-4.09 (2H, m), 4.66 (2H, s), 6.46 (1H, d, J = 8.0 Hz), 6.63 (1H, d, J = 8.3 Hz), 6.89 (1H, dd, J = 8.0, 8.3 Hz), 8.41 (1H, br) 127

¹H-NMR (CDCl₃) δ ppm: 1.80-2.00 (4H, m), 3.77 (2H, t, J = 6.4 Hz), 4.24 (2H, t, J = 5.8 Hz), 4.63 (2H, s), 6.55-6.70 (2H, m), 6.90 (1H, dd, J = 8.4, 8.4 Hz), 8.00 (1H, brs). 128

¹H-NMR (CDCl₃) δ ppm: 1.52 (6H, s), 1.90-2.10 (4H, m), 3.63 (2H, t, J = 6.3 Hz), 3.95 (2H, t, J = 5.8 Hz), 6.38 (1H, d, J = 2.8 Hz), 6.50 (1H, dd, J = 2.8, 8.7 Hz), 6.86 (1H, d, J = 8.8 Hz), 8.57 (1H, brs). 129

¹H-NMR (CDCl₃) δ ppm: 1.56 (3H, d, J = 6.8 Hz), 1.85-2.10 (4H, m), 3.61 (2H, t, J = 6.2 Hz), 3.94 (2H, t, J = 5.8 Hz), 4.59 (1H, q, J = 6.8 Hz), 6.38 (1H, d, J = 2.8 Hz), 6.49 (1H, dd, J = 2.8, 8.7 Hz), 6.88 (1H, d, J = 8.7 Hz), 8.60 (1H, brs). 130

¹H-NMR (DMSO- d₆) δ ppm: 1.81-2.10 (4H, m), 3.54-3.70 (2H, m), 3.89-4.03 (2H, m), 4.47 (2H, brs), 5.02 (1H, brs), 6.22 (1H, d, J = 2.4 Hz), 6.49 (1H, dd, J = 8.3, 2.4 Hz), 6.86-7.00 (2H, m).

Example 1 Synthesis of methyl 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylate

Methyl 5-(3-chloropropoxy)-1-methyl-1H-pyrazole-3-carboxylate (1.17 g, 5.0 mmol), 1-benzo[b]thiophen-4-yl piperazine hydrochloride (1.35 g, 5.3 mmol), potassium carbonate (1.74, 12.6 mmol) and sodium iodide (0.75 g, 5.0 mmol) were added to DMF (12 ml), and the mixture was stirred at 80° C. for 3 hours. The reaction solution was cooled to room temperature and water was added thereto, and then, extracted with ethyl acetate. The organic phase was washed with water and dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:3→dichloromethane:methanol=100:3). The purified product was concentrated under reduced pressure to obtain a light yellow oily substance (1.97 g). The oily substance was allowed to stand still at room temperature to obtain a solid substance, which was washed with diisopropyl ether and dried to obtain methyl 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylate (1.49 g).

Melting point: 109.0-110.5° C.

MS 414 (M⁺)

Example 2 Synthesis of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid

A 6N aqueous sodium hydroxide solution (2 ml) was added to an ethanol solution (10 ml) of methyl 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylate (1.62 g, 3.9 mmol) and the mixture was stirred at room temperature for 4 days. Then, 6N hydrochloric acid (2 ml) was added to the reaction solution under ice cooling and the solution mixture was stirred. Dichloromethane was added to the reaction solution and the precipitate was obtained by filtration. The filtrate was separated and the organic phase was concentrated under reduced pressure. The filter cake and the residue were combined, washed with water and dried to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid (1.53 g) as white powder.

Melting point: 114.5-118.0° C.

Example 3 Synthesis of N-methyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)]propoxy]-1-methyl-1H-pyrazole-3-carboxamide hydrochloride

A DMF solution of 5-[(3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid (0.3 g, 0.75 mmol) was cooled on ice and triethylamine (0.73 ml, 5.2 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol) and diethylphosphorocyanidate (DEPC) (0.25 ml, 1.4 mmol) were added thereto, and then, the mixture was stirred at room temperature for 24 hours. To the reaction solution, triethylamine (0.73 ml, 5.2 mmol), methylamine hydrochloride (0.3 g, 4.5 mmol) and DEPC (0.25 ml, 1.4 mmol) were added and the mixture was stirred at room temperature for 4 days. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extracted material was washed with water and dried over magnesium sulfate. The solution was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→ethyl acetate). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and a solution of 4N-hydrochloric acid/ethyl acetate was added thereto. The insoluble matter precipitated was obtained by filtration and dried to obtain N-methyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxamide hydrochloride (0.24 g) as white powder.

Melting point: 228.0-232.5° C. (dec)

Example 4 Synthesis of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxamide

The titled compound was obtained using 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid and ammonium chloride in the same manner as in Example 3.

White Powder (Ethyl Acetate-Diisopropyl Ether)

Melting point: 186.5-188.5° C.

Example 5 Synthesis of 4-[3-4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5,N-dimethylbenzamide

The titled compound was obtained using 4-(3-chloropropoxy)-3-methoxy-5,N-dimethylbenzamide and 1-benzo[b]thiophen-4-yl-piperazine hydrochloride in the same manner as in Example 1.

White Powder (Ethyl Acetate-Methanol)

Melting point: 141.5-142.5° C.

Example 6 Synthesis of N-methyl-2-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]thiazole-4-carboxamide hydrochloride

Sodium hydride (55%, oily, 90 mg, 2.2 mmol) was added to a DMF solution (2 ml) of 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propanol (0.2 g, 0.7 mmol) and N-methyl-2-chlorothiazole-4-carboxamide (0.26 g, 1.45 mmol) under ice cooling and the solution was stirred at 80° C. for 1.5 hours. After the reaction solution was cooled to room temperature and water was added thereto, it was extracted with ethyl acetate. The extraction solution with ethyl acetate was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=5:1→ethyl acetate). After the purified product was concentrated under reduced pressure, the residue was dissolved in ethyl acetate. A solution of 4N-hydrochloric acid/ethyl acetate was added to the solution and the insoluble matter precipitated was obtained by filtration and dried to obtain N-methyl-2-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]thiazole-4-carboxamide hydrochloride (0.24 g) as light yellow powder.

Melting point: 199.5-202.5° C.

Example 7 Synthesis of 2-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]thiazole-4-carboxamide

The titled compound was obtained using 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propanol (0.2 g, 0.7 mmol) and 2-chlorothiazole-4-carboxamide in the same manner as in Example 6.

White Powder (Ethyl Acetate-Diisopropyl Ether)

Melting point: 139.5-140.5° C.

Example 8 Synthesis of {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-carbamic acid tert-butyl ester

The titled compound was obtained using [4-(3-chloropropoxy)-3-methoxy-5-methylphenyl]-carbamic acid tert-butyl ester and 1-benzo[b]thiophen-4-yl-piperazine hydrochloride in the same manner as in Example 1.

Light Brown Oily Substance

¹H-NMR (CDCl₃) δppm: 1.51 (9H, s), 1.95-2.10 (2H, m), 2.24 (3H, s), 2.66-2.81 (6H, m), 3.14-3.31 (2H, m), 3.84 (3H, s), 3.95 (2H, t, J=6.3 Hz), 6.36 (1H, br), 6.60 (1H, d, J=2.5 Hz), 6.87-6.92 (1H, m), 7.01 (1H, d, J=2.0 Hz), 7.24-7.31 (1H, m), 7.37-7.44 (2H, m), 7.55 (1H, d, J=8.0 Hz)

MS 511 (M+).

Example 9 Synthesis of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline

6N-hydrochloric acid (3 ml) was added to a methanol solution (10 ml) of {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-carbamic acid tert-butyl ester (2.18 g, 4.3 mmol) and the mixture was stirred at room temperature overnight. After stirred at 60° C. for 15 minutes, the mixture was cooled to room temperature and a 6N aqueous sodium hydroxide solution was added thereto to neutralize it. Dichloromethane was added to the reaction mixture, and the substance extracted with dichloromethane was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2→ethyl acetate). The purified product was concentrated to dryness under reduced pressure to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline (1.26 g) as light yellow solid

Melting point: 155.0-158.0° C.

MS 411 (M⁺)

Example 10 Synthesis of N-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}formamide hydrochloride

4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline (0.9 g, 2.2 mmol) was added to ethyl formate (10 ml) and refluxed with heating for 33 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→ethyl acetate). The purified product was concentrated under reduced pressure and a solution of 4N-hydrochloric acid/ethyl acetate was added to an ethyl acetate solution of the residue. The insoluble matter precipitated was obtained by filtration to obtain N-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}formamide hydrochloride (0.3 g) as white powder.

Melting point: 247.5-253.0° C. (dec)

Example 11 Synthesis of N-methyl-4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline hydrochloride

A 6N aqueous sodium hydrochloride solution was added to N-{4-[(3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl formamide hydrochloride (0.23 g, 0.48 mmol) and the solution mixture was extracted with dichloromethane. The extraction solution with dichloromethane was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in a tetrahydrofuran (THF) solution (5 ml) and lithium aluminum hydride (30 mg, 0.71 mmol) was added thereto under ice cooling and refluxed with heating for 15 minutes. The reaction solution was cooled on ice, and water (0.03 ml), 15% aqueous sodium hydroxide solution (0.03 ml), and water (0.09 ml) were added to the reaction mixture in this order and stirred. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→3:1) and concentrated under reduced pressure. A solution of 4N-hydrochloric acid/ethyl acetate was added to an ethyl acetate solution of the residue, and the insoluble matter precipitated was obtained by filtration to obtain N-methyl-4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline hydrochloride (63 mg) as white powder.

Melting point: 239.5-244.0° C. (dec)

Example 12 Synthesis of 3-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}oxazolidin-2-one hydrochloride

The titled compound was obtained using 3-[4-(3-chloropropoxy)-3-methoxy-5-methylphenyl]oxazolidin-2-one and 1-benzo[b]thiophen-4-yl-piperazine hydrochloride in the same manner as in Example 1.

White Powder (Ethanol)

Melting point: 247.5-251.0° C. (dec)

Example 13 Synthesis of N-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}acetamide

The titled compound was obtained using N-[4-(3-chloropropoxy)-3-methoxy-5-methylphenyl]acetamide and 1-benzo[b]thiophen-4-yl-piperazine hydrochloride in the same manner as in Example 1.

White Powder (Ethyl Acetate-Diisopropyl Ether)

Melting point: 121.5-122.0° C.

Example 14 Synthesis of N-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-N-methylacetamide hydrochloride

Sodium hydride (55%, oily, 0.06 g, 1.3 mmol) was added to a DMF solution (5 ml) of N-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}acetamide (0.45 g, 0.99 mmol) under ice cooling and the mixture was stirred at 0° C. for 15 minutes. Methyl iodide (0.07 ml, 1.1 mmol) was added to the reaction solution and the solution was stirred at 0° C. for one hour. Further, sodium hydride (55% oily, 0.06 g, 1.3 mmol) and methyl iodide (0.07 ml, 1.1 mmol) were added to the reaction solution and the solution mixture was stirred at 0° C. for 2 hours. Water was added to the reaction solution and extraction was performed with ethyl acetate. The extracted material was washed with water, and dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→ethyl acetate). After the purified product was concentrated under reduced pressure, a solution of 4N-hydrochloric acid/ethyl acetate was added to an ethyl acetate solution of the residue. The insoluble matter precipitated was obtained by filtration to obtain N-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-N-methylacetamide hydrochloride (325 mg).

Melting point: 230.0-234.0° C. (dec)

Example 15 Synthesis of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-N,N-dimethyl-3-methoxy-5-methylaniline hydrochloride

Formalin (37%, 0.29 ml, 3.9 mmol) and sodium cyanoborohydride (0.21 g, 3.1 mmol) were added to a methanol solution (6 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylaniline (0.32 g, 0.78 mmol) under ice cooling and the mixture was stirred at 0° C. for 15 minutes. To the reaction solution, acetic acid (0.18 ml, 3.1 mmol) was added and the mixture was stirred at room temperature for one hour. An aqueous potassium carbonate solution was added to the reaction solution under ice cooling, and extraction was performed with ethyl acetate. The extracted material was dried over magnesium sulfate. The reaction solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=11:1→3:1). The purified product was concentrated under reduced pressure. A solution of 4N-hydrochloric acid and ethyl acetate was added to an ethyl acetate solution of the residue and the insoluble matter precipitated was obtained by filtration to obtain 4-[(3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-N,N-dimethyl-3-methoxy-5-methylaniline hydrochloride (137 mg) as white powder.

Melting point: 234.5-240.5° C. (dec)

Example 16 Synthesis of methyl {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}carbamate hydrochloride

The titled compound was obtained using methyl 4-(3-chloropropoxy)-3-methoxy-5-methylphenyl]carbamate and 1-benzo[b]thiophen-4-yl-piperazine hydrochloride in the same manner as in Example 1.

White Powder (Ethyl Acetate)

Melting point: 230.0-235.5° C.

Example 17 Synthesis of methyl N-methyl-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}carbamate hydrochloride

The titled compound was obtained using methyl {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}carbamate hydrochloride and methyl iodide in the same manner as in Example 14.

White Powder (Ethyl Acetate)

Melting point: 228.0-233.5° C.

Example 18 Synthesis of 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride

Lithium aluminum hydride (86 mg, 2.3 mmol) was suspended in THF (20 ml). To this solution, a THF solution (10 ml) of 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-benzo[1,4]oxazin-3-one (0.8 g, 1.9 mmol) was added dropwise under an argon atmosphere. After completion of dropwise addition, the solution mixture was refluxed with heating for one hour. Water (0.1 ml), 15% aqueous sodium hydroxide solution (0.1 ml), and water (0.3 ml) were added to the reaction mixture under ice cooling and stirred. Insoluble matter was removed by cerite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→20:1) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 ml) and a solution (0.34 ml) of 1N-hydrochloric acid/ethanol was added thereto and the mixture was stirred at room temperature for 15 minutes. The insoluble matter precipitated was obtained by filtration, washed with ethyl acetate, and dried to obtain 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (0.11 g) as white solid.

Melting point 207.9-208.8° C.

Example 19 Synthesis of 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride

The titled compound was obtained using 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-benzo[1,4]oxazin-3-one in the same manner as in Example 18.

Light Brown Solid (Ethyl Acetate)

Melting point: 214.0-215.9° C.

Example 20 Synthesis of 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride

Formalin (37%, 0.22 ml, 2.7 mmol) and MP-cyanoborohydride (2.41 mmol/g, 1.12 g, 2.7 mmol) were added to a methanol solution (15 ml) of 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-benzo[1,4]oxazine (0.30 g, 0.67 mmol) and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→50:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (15 ml) and a solution (0.64 ml) of 1N-hydrochloric acid/ethanol was added thereto. The mixture was stirred at room temperature for 15 minutes. The insoluble matter precipitated was obtained by filtration, washed with ethyl acetate, and dried to obtain 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (0.23 g) as light brown solid.

Melting point; 248.1-249.6° C.

Example 21 Synthesis of 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methyl-1,2,3,4-tetrahydroquinazolin-4-ol hydrochloride and 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methyl-1,2,3,4-tetrahydroquinazoline hydrochloride

A THF solution (20 ml) of 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methylquinazoline (0.25 g, 0.58 mmol) was cooled on ice. To this solution, a THF solution (5 ml) of lithium aluminum hydride (26 mg, 0.69 mmol) was added dropwise under an argon atmosphere. After completion of dropwise addition, the solution was stirred at room temperature for 20 minutes and refluxed with heating for one hour. Water (0.03 ml), 15% aqueous sodium hydroxide solution (0.03 ml), and water (0.1 ml) were added to the reaction solution under ice cooling and stirred. Insoluble matter was removed by cerite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→25:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (5 ml). To this, a solution (0.189 ml) of 1N-hydrochloric acid/ethanol was added and the mixture was stirred at room temperature for 15 minutes. The insoluble matter precipitated was obtained by filtration, washed with ethyl acetate, and dried to obtain 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methyl-1,2,3,4-tetrahydroquinazolin-4-ol hydrochloride (87 mg) as white solid.

MS: 438 (M⁺).

An eluting solution of dichloromethane/methanol (10:1) was passed through the column of the silica gel column chromatography. The obtained eluate was concentrated under reduced pressure and then the residue was dissolved in ethyl acetate (5 ml). To this, a solution (0.226 ml) of 1N-hydrochloric acid/ethanol was added and the mixture was stirred at room temperature for 15 minutes. The insoluble matter precipitated was obtained by filtration, washed with ethyl acetate, and dried to obtain 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methyl-1,2,3,4-tetrahydroquinazoline hydrochloride (49 mg) as white solid.

Melting point: 203.1-204.4° C.

Example 22 Synthesis of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2,3-dihydro-1H-indole hydrochloride

Triethylsilane (1.14 ml, 7.14 mmol) was added to a trifluoroacetic acid solution (5 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-indole (228 mg, 0.71 mmol) and the mixture was stirred at 50° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, neutralized by a saturated aqueous solution of sodium hydrogen carbonate and separated. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and a saturated saline solution in this order and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1). The purified product was concentrated under reduced pressure and the residue was added to ethyl acetate (5 ml) and a solution of 1N-hydrochloric acid/ethanol (0.10 ml) was added thereto and the mixture was stirred at room temperature for 15 minutes. The insoluble matter precipitated was obtained by filtration, washed with ethyl acetate, and dried to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2,3-dihydro-1H-indole hydrochloride (32 mg) as white solid.

Melting point: 222.4-223.9° C.

Compounds listed in the following Tables 13 to were produced using appropriate starting substances in the same manners as in Reference Examples 1 to 36 or Examples 1 to 22 and 3094 to 3110.

In the following Tables, compounds with the physical properties, such as crystalline form, m.p. (melting point), salt, ¹H-NMR and MS (mass spectrum), were prepared actually.

TABLE 13

Exam- Crystal form Melting point ple R1 (Recrystallization solvent) (° C.) Salt 23

White solid (Ethanol) 225-228 Trihydrochloride 24

White needle-form crystal (Ethanol/ethyl acetate) 165.0-167.0 Hydrochloride 25

White solid (Ethanol) 204-206 Hydrochloride 26

White powder (Ethyl acetate) 201.5-207.5 Hydrochloride 27

White powder (Ethyl acetate/isopropyl ether) 132.5-133.5 — 28

White powder (Ethyl acetate) 205.5-208.0 Hydrochloride 29

White powder (2-propanol) 206.5-208.0 — 30

Light yellow powder (Ethyl acetate) 201.5-204.0 Hydrochloride 31

White powder (Ethyl acetate) 155.5-162.0 Hydrochloride 32

White powder (Ethyl acetate) 140.0-141.5 Hydrochloride 33

Light yellow powder (Ethyl acetate) 192-194 dihydrochloride

TABLE 14

Exam- Crystal form Melting Point ple R1 (Recrystallization solvent) (° C.) Salt 34

Light yellow powder (Ethanol) 201-203 Dihydrochloride 35

White powder (Ethanol) 201-203 Hydrochloride 36

White powder (Ethanol) 214.0-215.0 Hydrochloride 37

White powder (Ethyl acetate/isopropyl ether) 131.5-132.0 — 38

White powder (Ethyl acetate) 193.0-194.0 — 39

White powder (Ethyl acetate/isopropyl ether) 128.0-129.5 — 40

White powder (Ethanol) 234.0-236.0 Hydrochloride 41

Light yellow powder (Ethyl acetate) 224.0-226.0 Dihydrochloride 42

White powder (water) 230.0 (dec) Hydrochloride 43

White powder (Ethyl acetate/isopropyl ether) 171.0-174.5 —

TABLE 15

Exam- Crystal form Melting point ple R1 (Recrystallization solvent) (° C.) Salt 44

Light yellow powder (Ethyl acetate) 166.0 (dec) Dihydrochloride 45

Light yellow powder (Ethyl acetate) 198.5-204.0 Dihydrochloride 46

White powder (Ethyl acetate) 211.5-214.5 Dihydrochloride 47

White powder (Ethanol) 241.0-243.0 Hydrochloride 48

White powder (Ethyl acetate/isopropyl ether) 150.0-150.5 — 49

White powder (Ethyl acetate) 199.0-200.5 Dihydrochloride 50

White powder (Ethyl acetate) 206.0-208.5 Hydrochloride 51

White powder (Ethyl acetate) 208.0-213.0 Hydrochloride 52

White powder (Ethanol) 157-159 Hydrochloride 53

White powder (Ethanol) 197.0-199.0 Dihydrochloride

TABLE 16

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 54

White powder (Ethanol) 205-207 Hydrochloride 55

White powder (Ethyl acetate) 178.0-182.5 Hydrochloride 56

Light yellow power (ethyl acetate) 191.5-195.5 Hydrochloride 57

Light yellow powder (Ethyl acetate/isopropyl ether) 112.0-115.5 — 58

White powder (Methanol) 205.0-209.5 Hydrochloride 59

White powder (Ethyl acetate/isopropyl ether) 149.5-151.0 — 60

Light yellow powder (Ethyl acetate/isopropyl ether) 114.5-115.5 — 61

White powder (Methanol) 116.5-118.0 — 62

White powder (Ethyl acetate) 210.5-214.5 Hydrochloride 63

Light yellow powder (Ethyl acetate/isopropyl ether) 109.0-110.0 —

TABLE 17

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 64

White powder (Ethanol/water) 129.0-131.0 — 65

White powder (Ethyl acetate) 247.5 (dec) Hydrochloride 66

White powder (Ethyl acetate) 231.0-234.0 Hydrochloride 67

White powder (Ethyl acetate) 245.5 (dec) Hydrochloride 68

White powder (Ethyl acetate) 199.5-201.5 Hydrochloride 69

White powder (Ethanol/water) 252.5-255.0 (dec) — 70

White powder (Ethyl acetate/isopropyl ether) 131.5-132.5 — 71

White powder (Ethyl acetate/isopropyl ether) 167.5-169.0 — 72

White powder (Ethyl acetate) 219.5-222.5 (dec) Hydrochloride 73

Light yellow powder (Ethyl acetate) 151.0-153.5 Hydrochloride 74

White powder (Ethyl acetate/isopropyl ether) 138.5-140.0 —

TABLE 18

Example R1 NMR Salt 75

¹H-NMR (DMSO-d₆) δ ppm: 2.10-2.30 (2H, m), 2.80-3.90 (16H, m), 4.09 (2H, t, J = 5.9 Hz), 6.88 (1H, d, J = 1.5 Hz), 6.96 (1H, d, J = 7.6 Hz), 7.17 (1H, d, J = 1.4 Hz), 7.31 (1H, dd, J = 7.8, 7.8 Hz), 7.48 (1H, d, J = 5.6 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.6 Hz), 10.68 (1H, brs). Hydrochloride 76

¹H-NMR (CDCl₃) δ ppm: 1.95-2.10 (2H, m), 2.62 (2H, t, J = 7.0 Hz), 2.65-2.80 (4H, m), 2.98 (3H, d, J = 4.9 Hz), 3.15-3.25 (4H, m), 4.05 (2H, t, J = 6.3 Hz), 5.94 (1H, brs), 6.43 (1H, d, J = 1.8 Hz), 6.90 (1H, dd, J = 1.4, 7.6 Hz), 7.15 (1H, d, J = 1.7 Hz), 7.20-7.35 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz). — 77

¹H-NMR (CDCl₃) δ ppm: 1.23 (3H, t, J = 7.3 Hz), 1.95-2.05 (2H, m), 2.61 (2H, t, J = 7.3 Hz), 2.65-2.80 (4H, m), 3.10-3.30 (4H, m), 3.40-3.55 (2H, m), 4.04 (2H, t, J = 6.3 Hz), 6.01 (1H, brs), 6.43 (1H, d, J = 1.6 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.16 (1H, d, J = 1.7 Hz), 7.27 (1H, dd, J = 7.8, 7.8 Hz), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz). — 78

¹H-NMR (CDCl₃) δ ppm: 1.95-2.10 (2H, m), 2.63 (2H, t, J = 7.3 Hz), 2.70-2.80 (4H, m), 3.15-3.25 (4H, m), 4.06 (2H, t, J = 6.3 Hz), 5.74 (2H, brs), 6.51 (1H, d, J = 1.7 Hz), 6.90 (1H, dd, J = 0.5, 7.6 Hz), 7.19 (1H, d, J = 1.7 Hz), 7.28 (1H, dd, J = 7.8, 7.8 Hz), 7.35-7.45 (2H, m), 7.56 (1H, d, J = 8.0 Hz). —

TABLE 19

Ex- Crystal form Melting am- (Recrystallization point ple R1 solvent) (° C.) Salt 79

White powder (Ethyl acetate/ ether) 183-186 Hydrochloride

TABLE 20

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 80

White powder (Ethanol/ethyl acetate) 183.0-185.0 Dihydrochloride 81

White powder (Ethanol/ethyl acetate) 205.0-207.0 Hydrochloride 82

White powder (Ethanol/ethyl acetate) 197.0-199.0 Hydrochloride 83

White powder (Ethyl acetate) 166.5-168.0 Hydrochloride 84

White powder (Ethyl acetate) 196.0-201.0 Hydrochloride 85

White powder (Ethyl acetate) 175.0-176.0 Hydrochloride 86

White powder (Ethyl acetate/isopropyl ether) 150.0-154.5 — 87

White powder (Ethyl acetate) 172.0-175.0 Hydrochloride 88

White Powder (Ethyl acetate/ether) 201-205 Hydrochloride

TABLE 21

Crystal form Melting Exam- (Recrystallization point ple R1 solvent) (° C.) Salt 89

White powder (Ethanol) 195-197 Hydro- chloride 90

White powder (Ethanol) 190-192 Hydro- chloride

TABLE 22

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 91

White powder (Ethyl acetate) 149-150 — 92

Light pink powder (Ethanol) 161-163 — 93

White solid (Ethyl acetate) 226.8-229.0 Hydrochloride 94

White solid (Ethyl acetate) 213.1-218.5 — 95

White solid (Ethyl acetate) 252.9-254.3 Hydrochloride 96

White solid (Ethyl acetate) 238.7-239.9 Hydrochloride 97

White solid (Ethyl acetate) 238.9-240.7 Hydrochloride 98

Light brown solid (Ethyl acetate) 218.4-220.4 Hydrochloride

TABLE 23

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt  99

White solid (Ethyl acetate) 267.0-271.0 Hydrochloride 100

White solid (Ethyl acetate/hexane) 143.8-145.2 — 101

White solid (Ethyl acetate) 250.6-252.1 Hydrochloride 102

White solid (Ethyl acetate) 233.3-235.2 Hydrochloride 103

White solid (Ethanol/ethyl acetate) 251.1-253.6 Hydrochloride 104

White solid (Ethyl acetate) 249.8-252.3 Hydrochloride 105

White solid (Ethyl acetate) 255.1-256.6 Hydrochloride 106

White solid (Ethyl acetate) 207.9-208.7 Hydrochloride 107

White solid (Ethyl acetate) 214.5-216.8 Hydrochloride

TABLE 24

Example R1 NMR Salt 108

¹H-NMR (CDCl₃) δ ppm: 2.04-2.13 (2H, m), 2.65 (2H, t, J = 7.2 Hz), 2.73 (4H, br), 3.19 (4H, br), 4.15 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 6.42 (1H, dd, J = 1.3, 8.0 Hz), 6.69 (1H, dd, J = 1.3, 8.3 Hz), 6.87-6.92 (2H, m), 7.25-7.30 (1H, m), 7.35-7.42 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 7.84 (1H, br) — 109

¹H-NMR (DMSO-d₆) δ ppm: 1.80-2.00 (2H, m), 2.45-2.55 (2H, m), 2.55-2.65 (4H, br), 3.00-3.10 (4H, br), 3.93 (2H, t, J = 6.3 Hz), 4.47 (2H, s), 6.45-6.55 (2H, m), 6.80-6.90 (2H, m), 7.26 (1H, t, J = 7.8 Hz), 7.38 (1H, d, J = 5.5 Hz), 7.60 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 5.5 Hz), 10.59 (1H, s) — 110

¹H-NMR (CDCl₃) δ ppm: 2.06 (2H, quint, J = 6.5 Hz), 2.66 (2H, t, J = 6.9 Hz), 2.70-2.80 (4H, m), 3.20-3.25 (4H, m), 4.12 (2H, t, J = 6.1 Hz), 4.60 (2H, s), 6.55-6.70 (2H, m), 6.88 (1H, d, J = 8.3 Hz), 6.91 (1H, d, J = 8.3 Hz), 7.20- 7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz), 8.43 (1H, brs) — 111

¹H-NMR (DMSO-d₆) δ ppm: 1.80-1.90 (2H, m), 2.41 (2H, t, J = 6.6 Hz), 2.50-2.55 (4H, m), 2.95-3.00 (4H, m), 3.83 (2H, t, J = 6.7 Hz), 6.47 (1H, dd, J = 2.4, 8.6 Hz), 6.70 (1H, d, J = 2.4 Hz), 6.85 (1H, d, J = 7.5 Hz), 7.09 (1H, d, J = 8.6 Hz), 7.27 (1H, dd, J = 7.9, 7.9 Hz), 7.36 (1H, d, J = 5.6 Hz), 7.60 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 5.6 Hz), 9.46 (1H, brs). — 112

¹H-NMR (DMSO-d₆) δ ppm: 1.88 (2H, t, J = 6.8 Hz), 2.50-2.55 (2H, m), 2.60 (4H, brs), 3.06 (4H, brs), 3.95 (2H, t, J = 6.4 Hz), 6.45- 6.55 (2H, m), 6.78 (1H, d, J = 9.1 Hz), 6.88 (1H, d, J = 7.7 Hz), 7.26 (1H, dd, J = 7.8, 7.8 Hz), 7.39 (1H, d, J = 5.6 Hz), 7.55-7.70 (2H, m), 10.35 (1H, brs), 10.49 (1H, brs). —

TABLE 25

Example R1 NMR Salt 113

¹H-NMR (DMSO-d₆) δ ppm: 2.20-2.30 (2H, m), 2.45-2.55 (2H, m), 3.00-3.80 (11H, m), 4.06 (2H, t, J = 5.9 Hz), 6.60-6.70 (2H, m), 6.90-7.00 (2H, m), 7.33 (1H, dd, J = 7.9, 7.9 Hz), 7.50 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.78 (1H, d, J = 5.5 Hz), 10.67 (1H, brs), 10.81 (1H, brs). Dihydrochloride 114

¹H-NMR (CDCl₃) δ ppm: 2.00-2.10 (4H, m), 2.70-2.85 (6H, m), 3.20-3.25 (4H, m), 3.40 (6H, s), 4.097 (2H, t, J = 6.3 Hz), 6.61 (1H, d, J = 2.2 Hz), 6.68 (1H, dd, J = 2.3, 8.4 Hz), 6.85 (1H, d, J = 8.5 Hz), 6.92 (1H, d, J = 7.6 Hz), 7.25-7.35 (1H, m), 7.35-7.45 (2H, m), 7.57 (1H, d, J = 8.0 Hz). — 115

¹H-NMR (DMSO-d₆) δ ppm: 2.25-2.35 (2H, m), 2.40 (3H, s), 3.20-3.70 (10H, m), 4.22 (2H, t, J = 5.9 Hz), 6.22 (1H, s), 6.95-7.05 (3H, m), 7.31 (1H, dd, J = 7.9, 7.9 Hz), 7.49 (1H, d, J = 5.5 Hz), 7.65-7.80 (3H, m), 10.93 (1H, brs). Hydrochloride 116

¹H-NMR (CDCl₃) δ ppm: 2.00-2.10 (2H, m), 2.60-2.70 (2H, m), 2.75 (4H, brs), 3.21 (4H, brs), 3.39 (3H, s), 4.05-4.15 (2H, m), 6.55- 6.70 (2H, m), 6.90 (1H, d, J = 7.6 Hz), 6.96 (1H, d, J = 8.5 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz), 9.12 (1H, brs) —

TABLE 25-1

Example R1 NMR Salt 117

¹H-NMR (CDCl₃) δ ppm: 2.10 (2H, t, J = 7.3 Hz), 2.70 (2H, t, J = 7.4 Hz), 2.77 (4H, brs), 3.22 (4H, brs), 3.80 (3H, s), 4.14 (2H, t, J = 6.3 Hz), 6.85-7.00 (3H, m), 7.25- 7.35 (1H, m), 7.35-7.45 (2H, m), 7.56 (1H, d, J = 8.1 Hz), 7.68 (1H, d, J = 8.8 Hz), 7.77 (1H, s). — 118

¹H-NMR (CDCl₃) δ ppm: 2.07 (2H, t, J = 7.0 Hz), 2.65 (2H, t, J = 7.2 Hz), 2.74 (4H, brs), 3.20 (4H, brs), 4.13 (2H, t, J = 6.3 Hz), 4.40 (2H, s), 6.38 (1H, brs), 6.90 (1H, d, J = 7.6 Hz), 6.97 (1H, s), 7.02 (1H, dd, J = 2.1, 8.4 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz), 7.78 (1H, d, J = 8.4 Hz). — 119

¹H-NMR (CDCl₃) δ ppm: 2.07 (2H, t, J = 7.0 Hz), 2.66 (2H, t, J = 5.7 Hz), 2.74 (4H, brs), 3.17 (3H, s), 3.20 (4H, brs), 4.12 (2H, t, J = 6.3 Hz), 4.31 (2H, s), 6.90 (1H, d, J = 7.6 Hz), 6.90-7.00 (2H, m), 7.25-7.30 (1H, m), 7.39 (1H, d, J = 5.5 Hz), 7.41 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 8.1 Hz), 7.74 (1H, d, J = 8.4 Hz) —

TABLE 25-2

Crystal form (Recrystallization Melting point Example R1 solvent) (° C.) Salt 120

White powder (Methanol) 242-246 Hydrochloride

TABLE 25-3

Example R1 NMR Salt 121

¹H-NMR (CDCl₃) δ ppm: 2.08 (2H, t, J = 7.3 Hz), 2.69 (2H, t, J = 7.4 Hz), 2.76 (4H, brs), 3.21 (4H, brs), 3.82 (3H, s), 4.13 (2H, t, J = 6.3 Hz), 6.91 (1H, d, J = 6.3 Hz), 6.99 (1H, dd, J = 2.3, 8.7 Hz), 7.25-7.35 (3H, m), 7.39 (1H, d, J = 5.6 Hz), 7.43 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.81 (1H, s). — 122

¹H-NMR (CDCl₃) δ ppm: 2.00-2.10 (2H, m), 2.65 (2H, t, J = 7.3 Hz), 2.74 (4H, brs), 3.21 (4H, brs), 4.13 (2H, t, J = 6.4 Hz), 4.40 (2H, s), 6.84 (1H, brs), 6.91 (1H, d, J = 7.5 Hz), 7.16 (1H, dd, J = 2.3, 8.3 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (4H, m), 7.55 (1H, d, J = 8.0 Hz). — 123

¹H-NMR (CDCl₃) δ ppm: 2.06 (2H, t, J = 7.2 Hz), 2.65 (2H, t, J = 7.3 Hz), 2.74 (4H, brs), 3.20 (7H, brs), 4.12 (2H, t, J = 6.4 Hz), 4.31 (2H, s), 6.91 (1H, d, J = 7.7 Hz), 7.10 (1H, dd, J = 2.4, 8.3 Hz), 7.25-7.35 (2H, m), 7.35 (1H, d, J = 2.3 Hz), 7.39 (1H, d, J = 5.5 Hz), 7.42 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 8.0 Hz). — 124

¹H-NMR (DMSO-d₆) δ ppm: 1.15 (3H, t, J = 7.3 Hz), 2.20-2.30 (2H, m), 3.15-3.30 (2H, m), 3.30-3.40 (4H, m), 3.45-3.70 (6H, m), 4.16 (2H, t, J = 5.8 Hz), 4.39 (2H, s), 6.97 (1H, d, J = 7.6 Hz), 7.10-7.25 (2H, m), 7.31 (1H, dd, J = 7.9, 7.9 Hz), 7.45-7.55 (2H, m), 7.69 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.6 Hz), 10.74 (1H, brs). Hydrochloride 125

¹H-NMR (DMSO-d₆) δ ppm: 2.20-2.30 (2H, m), 2.64 (2H, t, J = 5.8 Hz), 3.01 (2H, t, J = 5.5 Hz), 3.20-3.40 (6H, m), 3.53 (2H, d, J = 12.3 Hz), 3.64 (2H, d, J = 11.2 Hz), 4.15 (2H, t, J = 6.0 Hz), 6.95 (1H, d, J = 7.7 Hz), 7.13 (1H, d, J = 2.4 Hz), 7.25- 7.35 (2H, m), 7.45-7.55 (2H, m), 7.69 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.6 Hz), 11.12 (1H, brs). Hydrochloride

TABLE 26

Ex- Crystal form Melting am- (Recrystallization point ple R1 solvent) (° C.) Salt 126

Red-brown powder (Acetonitrile) 191-193 —

TABLE 27

Crystal form Example R1 (Recrystallization solvent) Melting point (° C.) Salt 127

Red-brown powder (Ethanol) 215-217 Hydrochloride 128

White solid (Ethyl acetate) 209.2-210.9 Hydrochloride 129

White solid (Ethanol/ethyl acetate) 242.0-244.9 Hydrochloride 130

White powder (Ethanol) 211-213 Hydrochloride 131

Light purple powder (Ethyl acetate) 180-182 — 132

Light pink powder (Ethanol) 170.2-171.9 — 133

White powder (Ethanol/ethyl acetate) 253-258 (dec) Hydrochloride 134

White powder (2-propanol) 213.7-220.6 Hydrochloride 135

White solid (Ethyl acetate) 152.6-155.3 Hydrochloride 136

White powder (Ethanol/ethyl acetate) 226-228 Hydrochloride

TABLE 28

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 137

White solid (Ethyl acetate) 238.8-241.8 Hydrochloride 138

White powder (Ethyl acetate/ether) 198-201 Hydrochloride 139

White powder (Ethyl acetate/ether) 206-209 Hydrochloride 140

White powder (Ethyl acetate/ether) 157-161 —

TABLE 29

Example R1 NMR Salt 141

¹H-NMR (DMSO-d₆) δ ppm: 1.75-1.85 (2H, m), 1.90-1.95 (2H, m), 3.05 (3H, s), 3.15-3.35 (6H, m), 3.55-3.65 (4H, m), 4.08 (2H, t, J = 6.1 Hz), 4.36 (2H, s), 6.95 (1H, d, J = 7.7 Hz), 7.10-7.20 (2H, m), 7.30 (1H, dd, J = 7.9, 7.9 Hz), 7.45-7.50 (2H, m), 7.69 (1H, d, J = 8.1 Hz), 7.75 (1H, d, J = 5.5 Hz), 10.75 (1H, brs). Dihydrochloride 142

¹H-NMR (DMSO-d₆) δ ppm: 1.70-1.80 (2H, m), 1.85-2.00 (2H, m), 3.22 (3H, s), 3.15-3.35 (6H, m), 3.45-3.60 (4H, m), 3.95 (2H, t, J = 6.1 Hz), 6.60-6.65 (2H, m), 6.90-7.00 (2H, m), 7.30 (1H, dd, J = 7.9, 7.9 Hz), 7.45-7.50 (1H, m), 7.68 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 10.82 (1H, s), 11.31 (1H, brs). Hydrochloride 143

¹H-NMR (CDCl₃) δ ppm: 1.52 (6H, s), 1.60-1.90 (4H, m), 2.53 (2H, t, J = 7.3 Hz), 2.70-2.80 (4H, m), 3.10-3.30 (4H, m), 3.97 (2H, t, J = 6.0 Hz), 6.37 (1H, d, J = 2.7 Hz), 6.53 (1H, dd, J = 2.7, 8.8 Hz), 6.85-6.95 (2H, m), 7.25-7.35 (2H, m), 7.35-7.45 (2H, m), 7.56 (1H, d, J = 8.0 Hz), 8.06 (1H, s) — 144

¹H-NMR (DMSO-d₆) δ ppm: 1.37 (3H, d, J = 6.7 Hz), 1.50-1.80 (4H, m), 2.41 (2H, t, J = 6.9 Hz), 2.55-2.65 (4H, br), 3.90 (2H, t, J = 6.2 Hz), 4.51 (1H, q, J = 6.7 Hz), 6.45-6.50 (2H, m), 6.80-6.90 (2H, m), 7.25 (1H, t, J = 7.8 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.59 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 5.5 Hz), 10.53 (1H, s) — 145

¹H-NMR (CDCl₃) δ ppm: 1.65-1.95 (4H, m), 2.53 (2H, t, J = 7.3 Hz), 2.70-2.75 (4H, m), 3.15-3.25 (4H, m), 4.08 (2H, t, J = 6.3 Hz), 4.61 (2H, s), 6.57 (1H, d, J = 8.3 Hz), 6.61 (1H, d, J = 8.3 Hz), 6.85- 6.95 (2H, m), 7.20-7.35 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 7.80 (1H, brs) — 146

¹H-NMR (CDCl₃) δ ppm: 1.60-1.88 (4H, m), 2.51 (2H, t, J = 7.5 Hz), 2.63-2.77 (4H, m), 3.13-3.25 (4H, m), 3.95 (2H, t, J = 6.3 Hz), 4.46 (2H, s), 5.28 (1H, brs), 6.25 (1H, d, J = 2.4 Hz), 6.50 (1H, dd, J = 8.4, 2.4 Hz), 6.90 (1H, d, J = 7.7 Hz), 6.92 (1H, d, J = 8.4 Hz), 7.27 (1H, dd, J = 7.8, 8.0 Hz), 7.38 (1H, d, J = 5.5 Hz), 7.41 (1H, d, J = 5.5 Hz), 7.51 (1H, brs), 7.54 (1H, d, J = 8.0 Hz). —

TABLE 30

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 147

White powder (Ethyl acetate) 143-144 — 148

Light yellow powder (Ethyl acetate/isopropyl ether) 112.5-114.5 — 149

White powder (Ethyl acetate) 208.0-211.5 Hydrochloride

TABLE 31

Example R1 NMR Salt 150

¹H-NMR (DMSO-d₆) δ ppm: 1.40-1.67 (2H, m), 1.73-1.90 (4H, m), 3.13-3.30 (6H, m), 3.52-3.62 (4H, m), 3.96-4.01 (2H, m), 4.54 (2H, s), 6.50 (1H, d, J = 7.7 Hz), 6.67 (1H, d, J = 7.3 Hz), 6.83-6.88 (1H, m), 6.96 (1H, d, J = 7.7 Hz), 7.28-7.34 (1H, m), 7.48 (1H, d, J = 5.6 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.6 Hz), 10.42 (1H, br), 10.67 (1H, br) Hydrochloride 151

¹H-NMR (DMSO-d₆) δ ppm: 1.40-1.60 (4H, m), 1.60-1.80 (2H, m), 2.35-2.45 (2H, m), 2.55-2.65 (4H, br), 3.90 (2H, t, J = 6.4 Hz), 4.49 (2H, s), 6.45-6.55 (2H, m), 6.80-6.95 (2H, m), 7.28 (1H, t, J = 7.8 Hz), 7.40 (1H, d, J = 5.6 Hz), 7.62 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 5.5 Hz), 10.61 (1H, s) — 152

¹H-NMR (CDCl₃) δ ppm: 1.45-1.70 (4H, m), 1.80-1.90 (2H, m), 2.45- 2.55 (2H, m), 2.65-2.75 (4H, m), 3.15-3.25 (4H, m), 4.05 (2H, t, J = 6.3 Hz), 4.61 (2H, s), 6.50-6.65 (2H, m), 6.85-6.95 (2H, m), 7.20-7.35 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 7.80 (1H, brs) —

TABLE 32

Example R1 NMR Salt 153

¹H-NMR (CDCl₃) δ ppm: 2.73 (4H, m), 3.19-3.20 (6H, m), 4.56 (2H, s), 4.54-4.62 (2H, m), 5.76-5.92 (2H, m), 6.38 (1H, d, J = 2.7 Hz), 6.54 (1H, dd, J = 8.8, 2.7 Hz), 6.89-6.92 (2H, m), 7.25 (1H, m), 7.39-7.41 (2H, m), 7.53-7.56 (2H, m) —

TABLE 33

Crystal form Example R1 R2 n (Recrystallization solvent) Melting point (° C.) Salt 154 —H —C₂H₅ 3 White powder 218.5-222.0 Hydrochloride (Ethyl acetate) (dec) 155 —H —C₃H₇ 3 Light yellow powder 127.0-128.5 — (Ethyl acetate/isopropyl ether) 156 —H —CH₃ 3 Light yellow powder 151.0-154.5 — (Ethyl acetate/isopropyl ether) 157 —CH₃ —CH₃ 3 White powder 206.5-211.5 Hydrochloride (Ethyl acetate) 158 —C₂H₅ —C₂H₅ 3 White powder 205.5-209.0 Hydrochloride (Ethyl acetate) 159 —H —CH₂CF₃ 3 White powder 217.0 Hydrochloride (Ethyl acetate) (dec) 160 —H —CH₂CH₂N(C₂H₅)₂ 3 White powder 229.5-232.5 Dihydrochloride (Ethyl acetate) 161 —H —CH₂CH₂OCH₃ 3 White powder 218.5-221.0 Hydrochloride (Ethyl acetate) 162 —H -cyclo-C₃H₅ 3 White powder 165.5-167.0 — (Ethyl acetate/isopropyl ether) 163 —H —CH(CH₃)₂ 3 White powder 131.5-132.5 — (Ethyl acetate/isopropyl ether) 164 —H —H 3 White powder 186.0-191.0 — (Dichloromethane) 165 —H —(CH₂)₅OH 3 White solid 202-203 Hydrochloride (Ethanol) 166 —H

3 Light brown solid 215-216 Hydrochloride (Ethanol) 167 —H —C₂H₅ 4 White powder 198.0-199.5 Hydrochloride (Ethyl acetate) 168 —H —CH₂CF₃ 4 White powder 194.5-196.0 Hydrochloride (Ethyl acetate) 169 —H —H 4 White powder 150.0-151.5 — (2-propanol) 170 —H —CH3 4 White powder 154.0-156.0 — (Ethyl acetate) 171 —CH3 —CH3 4 White powder 226.0 Hydrochloride (Ethyl acetate) (dec)

TABLE 34

Example R1 R2 NMR Salt 172 —H —CH₂CH₂OH ¹H-NMR (DMSO-d₆) Hydro- δ ppm: 2.1-2.2 (2H, m), chloride 3.1-3.8 (14H, m), 4.6- 4.17 (2H, t, J = 5.7 Hz), 4.8 (1H, br), 6.9-7.1 (3H, m), 7.33 (1H, dd, J = 7.9, 8.1 Hz), 7.51 (1H, d, J = 5.5 Hz), 7.72 (1H, d, J = 8.1 Hz), 7.78 (1H, d, J = 5.5 Hz), 7.86 (2H, d, J = 8.8 Hz), 8.2-8.3 (1H, br), 10.2-10.4 (1H, br).

TABLE 35

Crystal form Melting point Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) (° C.) Salt 173 —H —H —H —OCH₃ —CH₃ —CH₃ White powder 199.0-204.0 Hydrochloride (Ethyl acetate) 174 —OCH₃ —H —H —H —C₂H₅ —H White powder 162.0-163.0 — (Ethyl acetate/isopropyl ether) 175 —Cl —H —H —H —H —H White powder 154.0-155.5 — (Ethyl acetate/isopropyl ether) 176 —Cl —H —H —H —CH₃ —H White powder 145.0-148.0 — (Ethyl acetate/isopropyl ether) 177 —H —H —H —Cl —CH₃ —CH₃ White powder 213.0 Hydrochloride (Ethyl acetate) (dec) 178 —H —H —H —Cl —C₂H₅ —H White powder 211.0 Hydrochloride (Ethyl acetate) (dec) 179 —Cl —H —H —H —CH₂CF₃ —H White powder 128.5-131.0 — (Ethyl acetate/isopropyl ether) 180 —F —H —H —H —H —H White powder 153.5-156.0 — (Ethyl acetate/isopropyl ether)

TABLE 36

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 181 —H —H —H —F —CH₃ —H White powder 232.0 Hydrochloride (Ethyl acetate) (dec) 182 —H —H —H —F —CH₃ —CH₃ White powder 198.0-202.0 Hydrochloride (Ethyl acetate) 183 —H —H —H —F —C₂H₅ —H White powder 210.5-213.0 Hydrochloride (Ethyl acetate) 184 —F —H —H —H —CH₂CF₃ —H Light yellow powder 176.5-179.5 — (Ethyl acetate/isopropyl ether) 185 —CH₃ —H —H —H —H —H White powder 178.5-180.0 — (2-propanol) 186 —CH₃ —H —H —H —CH₃ —H White powder 156.5-158.0 — (2-propanol) 187 —H —H —H —CH₃ —CH₃ —CH₃ White powder 220.0-222.0 Hydrochloride (Ethyl acetate) (dec) 188 —CH₃ —H —H —H —C₂H₅ —H White powder 140.5-143.0 — (2-propanol) 189 —CH₃ —H —H —H —CH₂CF₃ —H White powder 154.5-157.0 — (2-propanol) 190 —OCH₃ —H —H —H —H —H White powder 162.0-163.5 — (2-propanol)

TABLE 37

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 191 —OCH₃ —H —H —H —CH₃ —H White powder 160.5-162.0 — (2-propanol) 192 —OCH₃ —H —H —H —CH₂CF₃ —H Light yellow powder 144.5-146.0 — (2-propanol) 193 —Cl —H —H —H —CH₂CH₂OCH₃ —H White powder 120-122 — 194 —H —H —H —F —CH₂CH₂OCH₃ —H White powder 215.0-217.0 Hydrochloride (Ethanol/ethyl acetate) 195 —CH₃ —H —H —H —CH₂CH₂OCH₃ —H White powder 120.0-121.0 — (Ethanol/hexane) 196 —H —H —H —OCH₃ —CH₂CH₂OCH₃ —H White powder 194-196 Hydrochloride (Ethanol/ethyl acetate) 197 —Br —H —H —H —H —H White powder 152.5-154.0 — (Ethyl acetate/isopropyl ether) 198 —Br —H —H —H —CH₃ —H White powder 148.0-150.0 — (Ethyl acetate/isopropyl ether) 199 —H —H —H —Br —CH₃ —CH₃ White powder 225.0 — (Ethyl acetate) (dec) 200 —H —H —H —Br —C₂H₅ —H Light yellow powder 214.5-220.5 Hydrochloride (Ethyl acetate) (dec)

TABLE 38

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 201 —H —H —H —Br —CH₂CF₃ —H White powder 230.0-234.5 Hydrochloride (Ethyl acetate/isopropyl ether) 202 —CN —H —H —H —H —H White powder 182.0-185.0 — (Ethyl acetate) 203 —CN —H —H —H —CH₃ —H White powder 177.5-181.5 — (2-propanol) 204 —H —H —H —CN —CH₃ —CH₃ White powder 213.5-214.0 Hydrochloride (Ethyl acetate) 205 —CN —H —H —H —C₂H₅ —H White powder 162.5-166.0 — (2-propanol) 206 —H —H —H —CN —CH₂CF₃ —H White powder 217.0-222.0 Hydrochloride (Ethyl acetate) 207 —H —Cl —H —H —H —H White powder 133.5-135.5 — (95% 2-propanol) 208 —H —Cl —H —H —CH₃ —H White powder 137.0-139.0 — (95% 2-propanol) 209 —H —H —Cl —H —CH₃ —CH₃ White powder 236.0 Hydrochloride (Ethyl acetate) (dec) 210 —H —H —Cl —H —C₂H₅ —H White powder 223.0-224.0 Hydrochloride (Ethyl acetate)

TABLE 39

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 211 —H —H —Cl —H —CH₂CF₃ —H White powder 210.5-216.0 Hydrochloride (Ethyl acetate) 212 —H —H —CF₃ —H —C₂H₅ —H White powder 212.0-219.5 Hydrochloride (Ethyl acetate) 213 —H —CF₃ —H —H —H —H White powder 139.5-141.0 Hydrochloride (Dichloromethane/isopropyl ether) 214 —H —H —CF₃ —H —CH₃ —H White powder 214.0-218.5 Hydrochloride (Ethyl acetate) 215 —H —H —CF₃ —H —CH₃ —CH₃ White powder 252.5 Hydrochloride (Ethyl acetate) (dec) 216 —H —H —CF₃ —H —CH₂CF₃ —H White powder 216.0-218.5 Hydrochloride (Ethyl acetate) 217 —H —OCH₃ —H —H —H —H White powder 173.5-178.5 — (2-propanol)

TABLE 39-1

Example R1 R2 R3 R4 R5 R6 NMR Salt 218 —N(CH₃)₂ —H —H —H —C₂H₅ —H 1H-NMR (CDCl₃) δ ppm: 1.20-1.30 (3H, m), 2.10-2.20 (2H, m), — 2.69 (2H, t, J = 7.3 Hz), 2.70-2.75 (4H, m), 2.85 (6H, s), 3.20-3.25 (4H, m), 3.45-3.55 (2H, m), 4.10-4.20 (2H, m), 6.00 (1H, brs), 6.85-6.95 (2H, m), 7.25-7.30 (3H, m), 7.35-7.45 (2H, m), 7.56 (1H, d, J = 8.1 Hz). 219 —NHCOCH₃ —H —H —H —C₂H₅ —H ¹H-NMR (CDCl₃ ) δ ppm: 1.20-1.30 (3H, m), 2.05-2.15 (2H, m), 2.25 — (3H, s), 2.65 (2H, t, J = 7.1 Hz), 2.70-2.80 (4H, m), 3.20-3.25 (4H, m), 3.40-3.55 (2H, m), 4.21 (2H, t, J = 6.4 Hz), 6.22 (1H, brs), 6.91 (1H, d, J = 7.7 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.56 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 8.5 Hz), 7.82 (1H, brs), 8.70 (1H, s).

TABLE 40

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 220 —H —H —OCH₃ —H —CH₃ —H White powder 221.5-223.0 Hydrochloride (2-propanol) 221 —H —H —OCH₃ —H —CH₃ —CH₃ White powder 207.5-215.0 Hydrochloride (Ethyl acetate) 222 —H —H —OCH₃ —H —C₂H₅ —H White powder 197.0-202.0 Hydrochloride (Ethyl acetate) 223 —H —H —OCH₃ —H —CH₂CF₃ —H White powder 219.0-227.0 Hydrochloride (Ethyl acetate) 224 —NO₂ —H —H —H —H —H Light yellow powder 157.5-161.0 — (Ethyl acetate/isopropyl ether) 225 —NO₂ —H —H —H —CH₃ —H Light yellow powder 157.5-161.5 — (Ethyl acetate/isopropyl ether) 226 —H —H —H —NO₂ —CH₂CF₃ —H Light yellow powder 217.5-219.5 Hydrochloride (Ethyl acetate) (dec) 227 —CF₃ —H —H —H —H —H White powder 163.5-165.5 — (95% 2-propanol) 228 —NH₂ —H —H —H —H —H White powder 172.5-173.0 — (Ethyl acetate/isopropyl ether) 229 —CF₃ —H —H —H —CH₃ —H White powder 158.5-162.0 — (95% 2-propanol) 230 —CF₃ —H —H —H —C₂H₅ —H White powder 146.5-148.5 — (95% 2-propanol)

TABLE 41

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 231 —CF₃ —H —H —H —CH₂CF₃ —H White powder 144.5-150.0 — (95% 2-propanol) 232 —NH₂ —H —H —H —CH₃ —H White powder 124.0-125.5 — (Ethyl acetate/isopropyl ether) 233 —N(CH₃)₂ —H —H —H —H —H White powder 143.0-145.0 — (Ethyl acetate/isopropyl ether) 234 —H —H —H —N(CH₃)₂ —CH₃ —H White powder 219.0-223.0 Hydrochloride (Ethyl acetate) 235 —NH₂ —H —H —H —CH₂CF₃ —H White powder 125.0-126.0 — (Ethyl acetate/isopropyl ether) 236 —N(CH₃)₂ —H —H —H —CH₂CF₃ —H White powder 147.5-148.5 — (Ethyl acetate/isopropyl ether) 237 —H —CH₃ —H —H —H —H White powder 150.5-152.5 — (95% 2-propanol) 238 —H —CH₃ —H —H —CH₃ —H White powder 138.0-139.0 — (95% 2-propanol) 239 —H —CH₃ —H —H —C₂H₅ —H White powder 137.5-139.0 — (95% 2-propanol) 240 —CH₃ —H —H —CH₃ —H —H White powder 167.0-168.0 — (95% 2-propanol)

TABLE 42

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 241 —CH₃ —H —H —CH₃ —CH₃ —H White powder 152.5-154.5 — (95% 2-propanol) 242 —CH₃ —H —H —CH₃ —C₂H₅ —H White powder 184.0-185.5 — (95% 2-propanol) 243 —OCH₃ —H —H —OCH₃ —H —H White powder 147.5-148.0 — (Ethyl acetate/isopropyl ether) 244 —OCH₃ —H —H —OCH₃ —CH₃ —H White powder 233.0-237.5 Hydrochloride (Ethyl acetate) (dec) 245 —OCH₃ —H —H —OCH₃ —C₂H₅ —H White powder 145.5-147.5 — (Ethyl acetate/isopropyl ether) 246 —OC₂H₅ —H —H —CH₃ —CH₃ —H White powder 186.5-188.0 Hydrochloride (Ethanol/ethyl acetate) 247 —CH₂CH═CH₂ —H —H —OCH₃ —H —H (Ethyl acetate/isopropyl ether) 126.0-130.0 — 248 —C₃H₇ —H —H —OCH₃ —H —H (Ethyl acetate/isopropyl ether) 137.5-140.0 — 249 —OCH₃ —H —H —CH₂CH═CH₂ —CH₃ —H White powder 180.5-186.0 Hydrochloride (Ethyl acetate) 250 —OCH₃ —H —H —C₃H₇ —CH₃ —H White powder 186.5-192.0 Hydrochloride (Ethyl acetate)

TABLE 43

Crystal form Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) Melting point (° C.) Salt 251 —CH₃ —H —H —OCH₃ —H —H White powder 156.0-157.0 — (Ethyl acetate/isopropyl ether) 252 —CH₃ —H —H —OCH₃ —CH₃ —H White powder 141.5-142.5 — (Ethyl acetate/methanol) 253 —OCH₃ —H —H —CH₃ —C₂H₅ —H White powder 220.5-224.5 Hydrochloride (Ethyl acetate) 254 —OCH₃ —H —H —CH₃ —CH₃ —OCH₃ White powder 223.0-227.5 Hydrochloride (Ethyl acetate)

TABLE 44

Example R1 R2 R3 R4 R5 R6 NMR Salt 255 —H —H —H —NO₂ —C₂H₅ —H 1H-NMR (CDCl3 ) δ ppm: 1.28 (3H, t, J = 7.3 Hz), 2.05-2.15 — (2H, m), 2.68 (2H, t, J = 7.0 Hz), 2.73 (4H, brs), 3.19 (4H, brs), 3.45-3.55 (2H, m), 4.29 (2H, t, J = 6.2 Hz), 6.14 (1H, brs), 6.90 (1H, d, J = 7.6 Hz), 7.18 (1H, d, J = 8.8 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d,J = 8.1 Hz), 8.04 (1H, dd, J = 2.3, 8.8 Hz

TABLE 45

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point (° C.) Salt 256 —H —H —H —H

White powder (Ethyl acetate) 234.5-238.0 Hydrochloride 257 —H —H —H —H

White powder (Ethyl acetate) 244.0 (dec) Dihydrochloride 258 —H —H —H —Cl

White powder (Ethyl acetate) 218.5-222.0 Hydrochloride 259 —H —H —H —Cl

White powder (Ethyl acetate) 255.0 (dec) Dihydrochloride 260 —H —H —H —F

White powder (Ethyl acetate) 224.5-227.5 (dec) Hydrochloride 261 —H —H —H —F

White powder (Ethyl acetate) 255.0 (dec) Dihydrochloride 262 —H —H —H —CH₃

White powder (Ethyl acetate) 236.0 (dec) Hydrochloride 263 —H —H —H —CH₃

White powder (Ethyl acetate) 255.5 (dec) Dihydrochloride 264 —H —H —H —OCH₃

White powder (Ethyl acetate) 226.0-228.0 (dec) Hydrochloride 265 —H —H —H —OCH₃

White powder (Ethyl acetate) 232.0 (dec) Dihydrochloride

TABLE 46

Example R1 R2 R3 R4 R5 R6 Crystal form (Recrystallization solvent) Melting point (° C.) Salt 266 —H —H —H —H —H —H Light yellow powder (Ethyl acetate/isopropyl ether) 158.0-160.0 — 267 —H —H —H —H —H —CH₃ Light yellow powder (Ethyl acetate) 183.0-186.0 Hydrochloride 268 —H —H —H —H —CH₃ —CH₃ Light yellow powder (Ethyl acetate) 158.0-161.5 Hydrochloride 269 —H —H —H —H —H —C₂H₅ Light yellow powder (Ethyl acetate) 168.5-173.0 Hydrochloride 270 —H —H —H —H —H —CH₂CF₃ Light yellow powder (Ethyl acetate/isopropyl ether) 187.5-189.0 Hydrochloride 271 —F —H —H —H —H —H White powder (Ethyl acetate/isopropyl ether) 156.5-159.0 — 272 —F —H —H —H —H —CH₃ White powder (Ethyl acetate/isopropyl ether) 214.5-218.0 Hydrochloride 273 —F —H —H —H —H —C₂H₅ White powder (Ethyl acetate) 211.0-218.0 Hydrochloride 274 —Cl —H —H —H —H —H White powder (Ethyl acetate/isopropyl ether) 139.0-140.5 — 275 —Cl —H —H —H —H —CH₃ White powder (Ethyl acetate) 218.5-222.5 Hydrochloride 276 —Cl —H —H —H —H —C₂H₅ White powder (Ethyl acetate) 247.0 (dec) Hydrochloride 277 —CH₃ —H —H —H —H —H White powder (Ethyl acetate/isopropyl ether) 129.5-130.0 — 278 —CH₃ —H —H —H —H —CH₃ White powder (Ethyl acetate/isopropyl ether) 148.5-151.0 — 279 —CH₃ —H —H —H —H —C₂H₅ White powder (Ethyl acetate/isopropyl ether) 133.0-134.5 — 280 —OCH₃ —H —H —H —H —H White powder (Ethyl acetate) 155.5-160.0 — 281 —OCH₃ —H —H —H —H —CH₃ White powder (Ethyl acetate) 163.5-165.0 Hydrochloride

TABLE 47

Example R1 R2 R3 R4 R5 R6 Crystal form (Recrystallization solvent) Melting point (° C.) Salt 282 —OCH₃ —H —H —H —H —C₂H₅ White powder (Ethyl acetate) 187.0-188.5 Hydrochloride 283 —OCH₃ —OCH₃ —H —H —H —H White powder (Ethyl acetate/isopropyl ether) 132.0-134.0 — 284 —OCH₃ —OCH₃ —H —H —H —CH₃ White powder (Ethyl acetate) 201.0-206.0 Hydrochloride 285 —OCH₃ —OCH₃ —H —H —H —C₂H₅ White powder (Ethyl acetate/isopropyl ether) 156.0-158.5 —

TABLE 48

Crystal form Melting point Example R1 R2 R3 R4 R5 R6 (Recrystallization solvent) (° C.) Salt 286 —H —H —H —H —C₂H₅ —H Light yellow powder (Ethyl acetate) 228.0-241.0 (dec) Dihydrochloride 287 —H —H —H —H —C₃H₇ —H White powder (Ethyl acetate) 232.0-236.0 (dec) Dihydrochloride 288 —H —H —H —H —C₃H₇ —CH₃ White powder (Ethyl acetate) 210.0-222.0 (dec) Dihydrochloride 289 —H —H —H —H —CH₃ —H White powder (Ethyl acetate) 235.5 (dec) Dihydrochloride 290 —H —H —H —H —CH₃ —CH₃ White powder (Ethyl acetate) 257.5 (dec) Dihydrochloride 291 —H —H —H —H —C₂H₅ —C₂H₅ White powder (Ethyl acetate) 232.0 (dec) Dihydrochloride 292 —H —H —H —H —CH₂CF₃ —H White powder (Ethyl acetate) 238.5-240.5 (dec) Dihydrochloride 293 —H —H —H —H —CH₂CH₂N(C₂H₅)₂ —H White powder (Ethyl acetate) 209.5 (dec) Triydrochloride 294 —H —H —H —H —H —H Light yellow powder (Ethyl acetate) 245.5 (dec) Dihydrochloride 295 —H —H —H —H —CHO —H White powder (Ethyl acetate) 207.5-213.0 Hydrochloride 296 —H —H —H —H —COCH₃ —CH₃ White powder (Ethyl acetate) 196.5-201.0 Hydrochloride 297 —H —H —H —H —COC₂H₅ —CH₃ White powder (Ethyl acetate) 194.5-198.0 Hydrochloride 298 —H —H —H —H —COC₆H₅ —CH₃ White powder (Ethyl acetate) 192.5-195.5 Hydrochloride 299 —H —H —H —H —CH₂C₆H₅ —CH₃ White powder (Ethyl acetate) 236.5 (dec) Dihydrochloride 300 —H —H —H —H —C₆H₅ —H White powder (Ethyl acetate) 191.0-193.5 Dihydrochloride 301 —OCH₃ —H —H —H —CH₃ —CH₃ White powder 101.0-103.0 — (Ethyl acetate/isopropyl ether) 302 —H —H —H —H —C₆H₅ —CH₃ White powder (Ethyl acetate) 207.5-214.5 Triydrochloride 303 —H —H —H —Cl —CH₃ —CH₃ White powder (Ethyl acetate) 259.0 (dec) Dihydrochloride 304 —H —H —H —F —CH₃ —CH₃ White powder (Ethyl acetate) 247.0 (dec) Dihydrochloride 305 —H —H —H —F —CH₃ —H White powder (Ethyl acetate) 237.0 (dec) Dihydrochloride 306 —H —H —H —F —CH₃ —COCH₃ White powder (Ethyl acetate) 196.0-199.0 Hydrochloride

TABLE 49

Example R1 R2 R3 R4 R5 R6 Crystal form (Recrystallization solvent) Melting point (° C.) Salt 307 —H —H —H —CH₃ —CH₃ —C₂H₅ White powder (Ethyl acetate) 256.5 (dec) Dihydrochloride 308 —H —H —H —CH₃ —CH₃ —H White powder (Ethyl acetate) 254.5 (dec) Dihydrochloride 309 —H —H —H —CH₃ —CH₃ —CH₃ White powder (Ethyl acetate) 277.5 (dec) Dihydrochloride 310 —H —H —H —CH₃ —COCH₃ —CH₃ White powder (Ethyl acetate) 230.0-232.0 (dec) Hydrochloride 311 —OCH₃ —H —H —H —CH₃ —H White powder (Ethyl acetate) 239.5 (dec) Dihydrochloride 312 —H —H —H —OCH₃ —CH₃ —COCH₃ White powder (Ethyl acetate) 206.0-211.5 Hydrochloride

TABLE 50

Example R1 R2 R3 R4 R5 Crystal form (Recrystallization solvent) Melting point (° C.) Salt 313 —H —H —H —H

White powder (Ethyl acetate) 243.5 (dec) Dihydrochloride 314 —H —H —H —H

White powder (Ethyl acetate) 261.5 (dec) Dihydrochloride 315 —H —H —H —Cl

White powder (Ethyl acetate) 249.0 (dec) Dihydrochloride 316 —H —H —H —Cl

White powder (Ethyl acetate) 253.5 (dec) Triydrochloride 317 —H —H —H —F

White powder (Ethyl acetate) 252.0 (dec) Dihydrochloride 318 —H —H —H —CH₃

White powder (Ethyl acetate) 242.0 (dec) Dihydrochloride

TABLE 51

Example R1 R2 R3 R4 R5 R6 Crystal form (Recrystallization solvent) Melting point (° C.) Salt 319 —H —H —H —H —C₂H₅ —C₂H₅ Light yellow powder (Ethyl acetate) 179.0-183.5 Hydrochloride 320 —H —H —H —H —H —H White powder (Ethyl acetate/water) 150.0-154.5 — 321 —H —H —H —H —H —CH₃ White powder (Ethyl acetate) 198.0-207.0 Hydrochloride 322 —H —H —H —H —CH₃ —CH₃ White powder (Ethyl acetate/isopropyl ether) 128.0-129.5 — 323 —H —H —H —H —H —C₂H₅ White powder (Ethyl acetate/isopropyl ether) 112.5-113.5 — 324 —H —H —H —H —H —CH₂CF₃ White powder (Ethyl acetate/isopropyl ether) 126.0-127.0 — 325 —Cl —H —H —H —H —H White powder (2-propanol) 161.5-166.0 — 326 —H —H —H —Cl —H —CH₃ White powder (Ethyl acetate) 194.5-197.0 Hydrochloride 327 —H —H —H —Cl —CH₃ —CH₃ White powder (Ethyl acetate) 197.5-201.0 Hydrochloride 328 —H —H —H —Cl —H —C₂H₅ White powder (Ethyl acetate) 227.5 (dec) Hydrochloride 329 —H —H —H —Cl —H —CH₂CF₃ (Ethyl acetate) 204.0-206.0 Hydrochloride 330 —OCH₃ —H —H —H —H —H White powder (Ethyl acetate/isopropyl ether) 129.0-130.0 — 331 —H —H —H —OCH₃ —H —CH₃ White powder (Ethyl acetate) 176.0-178.5 Hydrochloride 332 —H —H —H —OCH₃ —CH₃ —CH₃ White powder (Ethyl acetate) 188.5-192.0 Hydrochloride 333 —H —H —H —OCH₃ —H —C₂H₅ White powder (Ethyl acetate) 178.0-184.0 Hydrochloride 334 —H —H —H —OCH₃ —H —CH₂CF₃ Light yellow powder (Ethyl acetate) 187.5-192.0 Hydrochloride

TABLE 52

Example R1 R2 R3 R4 R5 R6 Crystal form (Recrystallization solvent) Melting point (° C.) Salt 335 —F —H —H —H —H —H White powder (2-propanol) 146.5-150.0 — 336 —H —H —H —F —H —CH₃ White powder (Ethyl acetate) 191.0-193.0 Hydrochloride 337 —H —H —H —F —CH₃ —CH₃ White powder (Ethyl acetate) 192.5-197.0 Hydrochloride 338 —H —H —H —F —H —C₂H₅ White powder (Ethyl acetate) 216.0-220.5 Hydrochloride 339 —H —H —H —F —H —CH₂CF₃ Light yellow powder (Ethyl acetate) 197.0-202.0 Hydrochloride 340 —H —H —H —H —H —H White powder (Ethyl acetate/isopropyl ether) 149.5-150.5 —

TABLE 53

Example R1 R2 R3 R4 R5 Crystal form (Recrystallization solvent) Melting point (° C.) Salt 341 —H —H —H —H

White powder (Ethyl acetate/isopropyl ether) 130.5-131.5 — 342 —H —H —H —H

White powder (Ethyl acetate) 227.5 (dec) Dihydrochloride

TABLE 54

Crystal form Melting point Example R1 R2 R3 R4 R5 (Recrystallization solvent) (° C.) Salt 343 —H —H —NHCOCH₃ —H —H White powder (Ethanol) 283.0-285.0 Hydrochloride 344 —H —H —NHCO₂CH₃ —H —H Light yellow powder 149.5-150.5 — (Ethyl acetate/isopropyl ether) 345 —H —H —NHSO₂C₂H₅ —H —H Light yellow powder (Ethanol/ethyl acetate) 174-176 Dihydrochloride 346 —H —H —NHC₂H₅ —H —H White powder (Ethyl acetate) 225 (dec) Hydrochloride 347 —H —H —N(CH₃)CO₂CH₃ —H —H White powder (Ethyl acetate) 196.0-202.0 Hydrochloride 348 —H —H —N(CH₃)COCH₃ —H —H White powder (Ethanol) 246-247 Hydrochloride 349 —H —H —NH₂ —H —H White powder (Ethanol containing water) 266-271 (dec) Hydrochloride 350 —H —H —NHCH₃ —H —H White powder (Ethanol) 264-266 Dihydrochloride 351 —H —H —N(CH₃)₂ —H —H White powder (Ethanol) 269-270 Dihydrochloride 352 —CH₃ —H —NH₂ —H —OCH₃ Light yellow solid (Ethyl acetate) 155.0-158.0 — 353 —OCH₃ —H —NHCON(CH₃)₂ —H —CH₃ White powder (Ethyl acetate) 206.0-210.0 Hydrochloride 354 —OCH₃ —H —NHCHO —H —CH₃ White powder (Ethyl acetate) 247.5-253.0 (dec) Hydrochloride 355 —OCH₃ —H —NHCO₂CH₃ —H —CH₃ White powder (Ethyl acetate) 230.0-235.5 Hydrochloride

TABLE 55

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point (° C.) Salt 356 —H —H

—H —H White powder (Ethyl acetate/2-propanol) 154.5-156.5 — 357 —H —H

—H —H White powder (2-propanol) 141.0-144.5 — 358 —OCH₃ —H

—H —CH₃ White powder (Ethanol) 247.5-251.0 (dec) Hydrochloride 359 —CH₂OH —H

—H —OCH₃ White powder (Ethanol) 144.0-145.0 Hydrochloride

TABLE 56

Example R1 R2 R3 R4 R5 NMR Salt 360 —H —H —NHCH(CH₃)₂ —H —H ¹H-NMR (DMSO-d₆) δ ppm: 1.24 (6H, d, J = 6.5 Hz), 2.2-2.4 (2H, m), Trihydrochloride 3.15-3.8 (12H, m), 4.15 (2H, t, J = 6 Hz), 6.99 (1H, d, J = 7.5 Hz), 7.11 (2H, d, J = 9 Hz), 7.33 (1H, dd, J = 8, 8 Hz), 7.4-7.55 (3H, m), 7.71 (1H, d, J = 8 Hz), 7.78 (1H, d, J = 5.5 Hz), 10.87 (3H, br). 361 —OCH₃ —H —NHCO₂CH₃ —H —H ¹H-NMR (CDCl₃) δ ppm: 2.00-2.15 (2H, m), 2.60-2.70 (2H, m), 2.73 — (4H, brs), 3.20 (4H, brs), 3.77 (3H, s), 3.88 (3H, s), 4.10 (2H, t, J = 6.6 Hz), 6.52 (1H, brs), 6.74 (1H, dd, J = 2.5, 8.6 Hz), 6.87 (1H, d, J = 8.6 Hz), 6.90 (1H, d, J = 7.7 Hz), 7.19 (1H, brs), 7.28 (1H, dd, J = 7.8, 7.8 Hz), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 7.8 Hz). 362 —H —H —NHCON(CH₃)₂ —H —H ¹H-NMR (DMSO-d₆) δ ppm: 2.20-2.30 (2H, m), 2.91 (6H, s), 3.20-3.40 Dihydrochloride (6H, m), 3.55 (2H, d, J = 12.4 Hz), 3.65 (2H, d, J = 11.4 Hz), 4.05 (2H, t, J = 6.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.98 (1H, d, J = 7.6 Hz), 7.30-7.40 (3H, m), 7.50 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.78 (1H, d, J = 5.5 Hz), 8.16 (1H, brs), 11.05 (1H, brs). 363 —F —H —NHCO₂CH₃ —H —H ¹H-NMR (DMSO-d₆) δ ppm: 2.24 (2H, brs), 3.10-3.25 (2H, m), Hydrochloride 3.30-3.50 (4H, m), 3.50-3.60 (2H, m), 3.66 (3H, s), 3.65-3.70 (2H, m), 4.13 (2H, t, J = 5.9 Hz), 6.98 (1H, d, J = 7.6 Hz), 7.10-7.20 (2H, m), 7.32 (1H, dd, J = 7.9, 7.9 Hz), 7.40 (1H, d, J = 13.3 Hz), 7.50 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 9.69 (1H, brs), 10.56 (1H, brs).

TABLE 56-1

Example R1 R2 R3 R4 R5 NMR Salt 364 —H —H —NHCONH₂ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.95-2.10 (2H, m), 2.64 (2H, t, J = 7.3 Hz), — 2.70-2.75 (4H, m), 3.15-3.20 (4H, m), 4.03 (2H, t, J = 6.3 Hz), 4.83 (2H, brs), 6.83 (1H, brs), 6.85-6.95 (3H, m), 7.20 (2H, d, J = 8.6 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz). 365 —H —H —NHCON(C₂H₅)₂ —H —H ¹H-NMR (DMSO-d₆) δ ppm: 1.06 (6H, t, J = 7.0 Hz), 2.15-2.30 (2H, Dihydrochloride m), 3.20-3.45 (10H, m), 3.54 (2H, d, J = 12 Hz), 3.64 (2H, d, J = 12 Hz), 4.03 (2H, t, J = 5.9 Hz), 6.84 (2H, d, J = 8.9 Hz), 6.97 (1H, d, J = 7.7 Hz), 7.25-7.40 (3H, m), 7.49 (1H, d, J = 5.6 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.6 Hz), 8.01 (1H, s), 10.95 (1H, s). 366 —H —H

—H —H ¹H-NMR (DMSO-d₆) δ ppm: 2.05-2.10 (2H, m), 2.67 (2H, t, J = 7.3 Hz), 2.76 (4H, brs), 3.22 (4H, brs), 4.11 (2H, t, J = 6.3 Hz), 6.91 (1H, d, J = 7.6 Hz), 7.01 (2H, d, J = 8.9 Hz), 7.20 (2H, d, J = 9.6 Hz), 7.25-7.35 (3H, m), 7.35-7.45 (2H, m), 7.56 (1H, d, J = 8.0 Hz), 7.77 (1H, s). — 367 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 2.05-2.15 (2H, m), 2.67 (2H, t, J = 7.2 Hz), 2.75 (4H, brs), 3.21 (4H, brs), 4.12 (2H, t, J = 6.3 Hz), 6.91 (1H, d, J = 7.6 Hz), 7.00-7.05 (2H, m), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.50-7.60 (3H, m), 8.08 (1H, s), 8.45 (1H, s). —

TABLE 57

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point (° C.) Salt 368 —H —H —CH₂CH₂N(C₂H₅)₂ —H —H White powder 224.0-232.0 Dihydrochloride (Ethyl acetate) (dec) 369 —H —H —H —NHCO₂CH₃ —H White powder 178.0-181.0 Hydrochloride (Ethyl acetate) (dec) 370 —H —H —CN —H —H Light yellow powder 105.5-107.0 — (Ethyl acetate/isopropyl ether) 371 —H —H —CO₂H —H —H White powder 263.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 372 —H —H —CO₂CH₃ —H —OCH₃ White powder 242.0 Hydrochloride (Ethyl acetate) (dec) 373 —H —H —Br —H —H White powder 119.0-120.0 — (Ethyl acetate/isopropyl ether) 374 —OCH₃ —H —CO₂H —H —H White powder 121.0-124.5 — (Water) 375 —Cl —H —CO₂C₂H₅ —H —H Light yellow powder 122.0-123.5 — (Ethanol/isopropyl ether) 376 —H —H —CH₂CO₂CH₃ —H —H White powder 213.5-221.5 Hydrochloride (Ethyl acetate) (dec) 377 —H —H —CO₂C₂H₅ —H —F White powder 231.5-233.5 Hydrochloride (Ethyl acetate)

TABLE 58

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point (° C.) Salt 378 —H —H —CO₂H —H —Cl White powder 273.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 379 —H —H —CH₂CO₂H —H —H White powder 217.0-222.0 Hydrochloride (Hydrochloric acid/acetic acid) 380 —H —H —CO₂H —H —F White powder 267.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 381 —H —H —CH₂CH₂NHCH₃ —H —H White powder 258. 0 Dihydrochloride (Ethyl acetate) (dec) 382 —H —H —CH₂CH₂N(CH₃)₂ —H —H White powder 236.5 Dihydrochloride (Ethyl acetate) (dec) 383 —H —H —CH₂CH₂N(CH₃)COCH₃ —H —H White powder 215.0-217.0 Hydrochloride (Ethyl acetate) 384 —H —H —CH₂CH₂N(CH₃)COC₂H₅ —H —H White powder 211.0-217.0 Hydrochloride (Ethyl acetate) 385 —H —H —CH₂CH₂N(CH₃)COC₆H₅ —H —H White powder 210.5-212.0 Hydrochloride (Ethyl acetate) 386 —H —H —CH₂CH₂N(CH₃)CH₂C₆H₅ —H —H White powder 196.0-202.0 Dihydrochloride (Ethyl acetate) (dec) 387 —H —H —CH₂CH₂NHC₂H₅ —H —H White powder 230.0 Dihydrochloride (Ethyl acetate/isopropyl ether) (dec)

TABLE 59

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point (° C.) Salt 388 —H —H —CH₂CH₂NHCH₂CF₃ —H —H White powder 223.0 Dihydrochloride (Ethyl acetate) (dec) 389 —H —H —CH₂CO₂C₂H₅ —H —Cl White powder 225.0-228.5 Hydrochloride (Ethyl acetate) 390 —H —H —CH₂CO₂H —H —Cl White powder 208.0-209.5 Hydrochloride (Hydrochloric acid/acetic acid) 391 —H —H —CH₂CO₂C₂H₅ —H —OCH₃ White powder 205.5-213.5 Hydrochloride (Ethyl acetate) 392 —CH₃ —H —CN —H —H Light yellow powder 105.5-106.0 — (Ethyl acetate/isopropyl ether) 393 —H —H —CH₂CO₂H —H —OCH₃ White powder 198.5-201.0 Hydrochloride (Hydrochloric acid/acetic acid) 394 —H —H —SO₂NH₂ —H —H White powder 199.0-203.0 — (Ethanol) 395 —H —H —CO₂H —H —CH₃ White powder 280.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 396 —H —H —CH₂CO₂C₂H₅ —H —F White powder 220.5-224.0 Hydrochloride (Ethyl acetate) 397 —H —H —CH₂CO₂H —H —F White powder 181.5-184.5 Hydrochloride (Hydrochloric acid/acetic acid)

TABLE 60

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point (° C.) Salt 398 —H —H —CN —OCH₃ —H White powder 238.0 Hydrochloride (Ethyl acetate) (dec) 399 —H —H —CO₂C₂H₅ —H —Br White powder 237.5-242.5 Hydrochloride (Ethyl acetate) (dec) 400 —H —CN —H —H —H White powder 217.5-221.0 Hydrochloride (Ethyl acetate) (dec) 401 —H —H —CO₂H —H —Br White powder 271.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 402 —H —H —H —CO₂H —H White powder 242.5-244.5 Hydrochloride (Hydrochloric acid/acetic acid) 403 —H —H —H —H —CN White powder 221.5-226.0 Hydrochloride (Ethyl acetate) 404 —CN —H —CO₂C₂H₅ —H —H White powder 128.5-130.0 — (Ethyl acetate/isopropyl ether) 405 —H —H —CO₂H —H —CN White powder 271.0 Hydrochloride (Dichloromethane/water) (dec) 406 —CONHC₂H₅ —H —H —H —H White powder 220.0-227.5 Hydrochloride (Ethyl acetate) 407 —H —H —CO₂C₂H₅ —CF₃ —H White powder 224.5-232.0 Hydrochloride (Ethyl acetate)

TABLE 61

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 408 —H —H —CO₂C₂H₅ —Cl —H White powder 216.5-219.0 Hydrochloride (Ethyl acetate) 409 —H —H —CO₂H —Cl —H White powder 259.0 Hydrochloride (Ethyl acetate) (dec) 410 —H —OCH₃ —CHO —H —H White powder 118.0-119.5 — (Ethyl acetate 2-propanol) 411 —H —H —CO₂H —CF₃ —H White powder 240.0 Hydrochloride (Water) (dec) 412 —H —H —CN —CH₃ —H White powder 230.0-237.0 Hydrochloride (Ethyl acetate) 413 —NO₂ —H —CO₂C₂H₅ —H —H Light yellow powder 113.0-114.0 — (Ethyl acetate/isopropyl ether) 414 —H —H —CHO —H —H White powder 102.5-105.5 — (Ethyl acetate) 415 —H —H —CO₂H —H —NO₂ White powder 259.0 Dihydrochloride (Hydrochloric acid/acetic acid) (dec) 416 —H —H —CH═CHCO₂H —H —H White powder 265.0 Hydrochloride (Hydrochloric acid/water) (dec) 417 —H —H —CO₂C₂H₅ —H —CF₃ White powder 211.5-221.0 Hydrochloride (Ethyl acetate)

TABLE 62

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 418 —H —H —CO₂H —H —CF₃ White powder 269.0 Hydrochloride (Ethyl acetate) (dec) 419 —H —CH₂CO₂C₂H₅ —H —H —H White powder 206.0-208.0 Hydrochloride (Ethyl acetate) 420 —H —H —CH═CHCONH₂ —H —H White powder 210.5-215.0 — (Ethyl acetate) 421 —H —CH₂CO₂H —H —H —H Light brown powder 255.0 Hydrochloride (Ethyl acetate) (dec) 422 —H —H —CH═CHCONHCH₃ —H —H White powder 165.5-169.0 — (95%-2-propanol) 423 —H —H —CH═CHCON(CH₃)₂ —H —H White powder 130.5-131.5 — (95%-2-propanol) 424 —H —H —CH═CHCONHC₂H₅ —H —H White powder 158.0-159.0 — (95%-2-propanol) 425 —H —H —CH═CHCONHCH₂CF₃ —H —H White powder 177.5-180.0 — (95%-2-propanol) 426 —H —H —(CH₂)₂CO₂C₂H₅ —H —H White powder 235.0-237.5 Hydrochloride (Ethyl acetate) 427 —F —H —H —CO₂C₂H₅ —H White powder 218.5-224.0 Hydrochloride (Ethyl acetate)

TABLE 63

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 428 —H —H —CH₂CH₂CO₂H —H —H White powder 240.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 429 —F —H —H —CO₂H —H White powder 260.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 430 —Cl —H —H —CO₂C₂H₅ —H White powder 241.0-245.0 Hydrochloride (Ethyl acetate) 431 —Cl —H —H —CO₂H —H White powder 268.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 432 —CH₃ —H —H —CO₂C₂H₅ —H White powder 238.0-242.0 Hydrochloride (Ethyl acetate) (dec) 433 —CH₃ —H —CO₂C₂H₅ —H —CH₃ White powder 106.0-108.0 — (isopropyl ether) 434 —CH₃ —H —H —CO₂H —H White powder 256.5 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 435 —CH₃ —H —CO₂H —H —CH₃ White powder 252.5 Hydrochloride (Water) (dec) 436 —OCH₃ —OCH₃ —H —CO₂C₂H₅ —H White powder 225.0-234.0 Hydrochloride (Ethyl acetate) 437 —H —H —C(CH₃)₂CO₂CH₃ —H —H White powder 222.0-226.5 Hydrochloride (Ethyl acetate)

TABLE 64

Ex- Crystal form Melting ample R1 R2 R3 R4 R5 (Recrystallization solvent) point(° C.) Salt 438 —OCH₃ —H —H —CO₂C₂H₅ —H White powder 208.0-213.5 Hydrochloride (Ethyl acetate) 439 —H —H —C(CH₃)₂CO₂H —H —H White powder 257.5 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 440 —H —H —CH₂CH₂CONH₂ —H —H Light yellow powder 167.5-170.0 — (95%-2-propanol) 441 —H —H —CH₂CH₂CONHCH₃ —H —H White powder 128.0-132.0 — (95%-2-propanol) 442 —OCH₃ —H —H —CO₂H —H White powder 250.0 Hydrochloride (Hydrochloric acid/water) (dec) 443 —H —H —CH₂CH₂CONHC₂H₅ —H —H White powder 130.5-132.0 Hydrochloride (95%-2-propanol) 444 —H —CH₂CONH₂ —H —H —H White powder 132.5-134.0 Hydrochloride (Ethyl acetate/isopropyl ether) 445 —H —H —H —CH₂CONHCH₃ —H White powder 173.5-175.0 Hydrochloride (Ethyl acetate) 446 —OCH₃ —OCH₃ —H —CO₂H —H White powder 154.0-155.5 Hydrochloride (Water) 447 —OCH₃ —H —CO₂C₂H₅ —H —OCH₃ White powder 239.0-242.0 Hydrochloride (Ethyl acetate) (dec)

TABLE 65

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 448 —OCH₃ —H —CO₂H —H —OCH₃ White powder 191.0-196.0 — (Water) 449 —H —H —CSNHC₂H₅ —H —H Light yellow powder 193.0-196.5 Dihydrochloride (Ethyl acetate/THF) 450 —OCH₃ —H —COCH₃ —H —CH₃ White powder 243.0 Hydrochloride (Ethyl acetate) (dec) 451 —CH₂CH═CH₂ —H —CO₂H —H —OCH₃ White powder  97.0-102.0 — (Water) 452 —C₃H₇ —H —CO₂H —H —OCH₃ White powder 145.5-150.5 — (Water)

TABLE 66

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 453 —H —H

—H —H White powder (Ethyl acetate/isopropyl ether) 112.5-113.5 — 454 —H —H

—H —H White powder (Ethyl acetate/isopropyl ether) 112.0-113.0 —

TABLE 67

Example R1 R2 R3 R4 R5 NMR Salt 455 —H —H —F —H —H Hydrochloride 456 —H —H —H —H —H ¹H-NMR (DMSO-d₆) δ ppm: 2.15-2.30 (2H, m), Hydrochloride 3.10-3.25 (2H, m), 3.25-3.60 (4H, m), 3.55-3.75 (4H, m), 4.10 (2H, t, J = 6.0 Hz), 6.90-7.10 (4H, m), 7.25-7.40 (3H, m), 7.51 (1H, d, J = 5.6 Hz), 7.72 (1H, d, J = 8.3 Hz), 7.78 (1H, d, J = 5.5 Hz), 10.12 (1H, brs). Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 457 —H —H —H —H —NHCOCH₃ Colorless needle-form crystal 243.7-244.8 — (Ethanol)

TABLE 67-1

Example R1 R2 R3 R4 R5 NMR Salt 458 —H —H —COCH₃ —H —OCH₃ ¹H-NMR (DMSO-d₆) δ ppm: 2.20-2.40 (2H, m), Hydrochloride 2.53 (3H, s), 3.20-3.70 (10H, m), 3.83 (3H, s), 4.19 (2H, t, J = 5.8 Hz), 6.96 (1H, d, J = 7.5 Hz), 7.10 (1H, d, J = 8.5 Hz), 7.31 (1H, t, J = 7.8 Hz), 7.45-7.50 (2H, m), 7.62 (1H, dd, J = 2.0, 8.4 Hz), 7.69 (1H, d, J = 8.0 Hz), 7.76 (1H, d, J = 5.5 Hz), 11.14 (1H, brs). 459 —OCH₃ —H —H —H —OCH₃ Hydrochloride 460 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 1.95-2.10 (6H, m), 2.60-2.75 (7H, m), 2.96 (2H, t, J = 11.3 Hz), 3.21 (4H, brs), 3.55 (2H, d, J = 12.4 Hz), 4.06 (2H, t, J = 6.2 Hz), 6.80-6.95 (3H, m), 7.17 (2H, d, J = 8.5 Hz), 7.25-7.35 (1H, m), 7.40 (1H, d, J = 5.5 Hz), 7.43 (1H, d, J = 5.6 Hz), 7.57 (1H, d, J = 8.1 Hz). — 461 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 1.55-1.65 (2H, m), 1.80-1.95 (2H, m), 2.00-2.10 (2H, m), 2.13 (3H, s), 2.55-2.75 (7H, m), 3.10-3.20 (6H, m), 3.93 (1H, d, J = 13.7 Hz), 4.05 (2H, t, J = 6.4 Hz), 4.78 (1H, d, J = 13.3 Hz), 6.85-6.95 (3H, m), 7.11 (2H, d, J = 8.6 Hz), 7.25-7.30 (1H, m), 7.39 (1H, d, J = 5.6 Hz), 7.42 (1H, d, J = 5.5 Hz), 7.55 (1H, d, J = 8.1 Hz). — 462 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 1.75-1.85 (4H, m), 2.00-2.10 (4H, m), 2.32 (3H, s), 2.35-2.45 (1H, m), 2.63 (2H, t, J = 7.4 Hz), 2.73 (4H, brs), 2.96 (2H, d, J = 11.5 Hz), 3.20 (4H, brs), 4.04 (2H, t, J = 6.3 Hz), 6.85-6.95 (3H, m), 7.14 (2H, d, J = 8.6 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz). —

TABLE 68

Example R1 R2 R3 R4 R5 NMR Salt 463 —H —H —F —H —H ¹H-NMR (DMSO-d₆) δ ppm: 3.10-3.25 (2H, m), 3.40-3.75 (8H, m), Hydrochloride 4.40-4.45 (2H, m), 6.98 (1H, d, J = 7.7 Hz), 7.00-7.25 (4H, m), 7.33 (1H, dd, J = 7.9, 7.8 Hz), 7.50 (1H, d, J = 5.6 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.78 (1H, d, J = 5.5 Hz), 10.37 (1H, brs). 464 —H —H —H —H —H ¹H-NMR (DMSO-d₆) δ ppm: 3.10-3.35 (2H, m), 3.40-3.80 (8H, m), Hydrochloride 4.48 (2H, t, J = 4.8 Hz), 6.95-7.10 (4H, m), 7.25-7.40 (3H, m), 7.51 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 5.5 Hz), 10.80-11.20 (1H, br).

TABLE 69

Example R1 R2 R3 R4 R5 NMR Salt 465 —H —H —H —H —H ¹H-NMR (DMSO-d₆) δ ppm: 1.70-2.00 (4H, m), 3.10-3.40 (6H, m), Hydrochloride 3.50-3.80 (4H, m), 4.03 (2H, t, J = 5.9 Hz), 6.90-7.00 (5H, m), 7.25-7.40 (3H, m), 7.50 (1H, d, J = 5.6 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 10.59 (1H, brs) 466 —H —H —F —H —H ¹H-NMR (DMSO-d₆) δ ppm: 1.75-1.95 (4H, m), 3.10-3.50 (6H, m), Hydrochloride 3.50-3.65 (4H, m), 4.00 (2H, t, J = 5.9 Hz), 6.90-7.00 (3H, m), 7.00-7.20 (2H, m), 7.32 (1H, dd, J = 7.9, 7.8 Hz), 7.50 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 10.40-10.60 (1H, br). 467 —H —H —COCH₃ —H —OCH₃ ¹H-NMR (DMSO-d₆) δ ppm: 1.80-1.95 (4H, m), 2.52 (3H, s), Hydrochloride 3.20-3.35 (6H, m), 3.50-3.65 (4H, m), 3.83 (3H, s), 4.00-4.15 (2H, m), 6.95 (1H, d, J = 7.5 Hz), 7.08 (1H, d, J = 8.5 Hz), 7.30 (1H, dd, J = 7.8, 7.8 Hz), 7.40-7.50 (2H, m), 7.61 (1H, dd, J = 1.9, 8.4 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.75 (1H, d, J = 5.6 Hz), 11.0 (1H, brs).

TABLE 69-1

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 468 —H —H —NHCO₂CH₃ —H —H White powder 241.0 Hydrochloride (Ethyl acetate) (dec) 469 —H —H —H —NHCO₂CH₃ —H White powder 203.0-209.5 Hydrochloride (Ethyl acetate) 470 —H —H —CN —H —H White powder 220.0-223.0 Hydrochloride (Ethyl acetate) (dec) 471 —H —H —CO₂H —H —H White powder 247.5-250.0 Hydrochloride (Hydrochloric acid/acetic acid) (dec) 472 —H —CN —H —H —H White powder 196.0-198.5 Hydrochloride (Ethyl acetate) 473 —H —H —H —CO₂H —H White powder 255.5-258.5 Hydrochloride (Ethyl acetate) 474 —CN —H —H —H —H White powder 187.5-188.5 Hydrochloride (Ethyl acetate) 475 —H —H —H —CONHCH₂CF₃ —H White powder 137.0 Hydrochloride (Ethyl acetate/2-propanol) (dec) 476 —H —H —H —CONHC₂H₅ —H Light yellow powder 130.0-135.0 Hydrochloride (Ethyl acetate/2-propanol) 477 —H —H —H —H —CO₂H White powder 192.0-197.0 Hydrochloride (Dichloromethane/water) 478 —H —CONH₂ —H —H —H Light yellow powder 148.0-151.0 — (2-propanol)

TABLE 69-2

Crystal form Example R1 R2 R3 R4 R5 (Recrystallization solvent) Melting point(° C.) Salt 479 —H —H —H —CONHCH₃ —H Light yellow powder 234.0-239.0 Hydrochloride (Ethyl acetate) 480 —H —H —H —CON(CH₃)₂ —H Light yellow powder 135.0-141.5 Hydrochloride (Ethyl acetate) 481 —H —H —H —H —CONHC₂H₅ White powder 209.5-213.0 Hydrochloride (Ethyl acetate)

TABLE 70

Example R1 NMR Salt 482

¹H-NMR (CDCl₃) δ ppm: 2.00-2.10 (2H, m), 2.63 (2H, t, J = 7.3 Hz), 2.70-2.80 (4H, m), 3.15-3.25 (4H, m), 3.89 (3H, s), 4.00-4.10 (2H, m), 6.57 (1H, d, J = 1.9 Hz), 6.91 (1H, d, J = 7.6 Hz), 7.20-7.35 (2H, m), 7.35-7.50 (3H, m), 7.56 (1H, d, J = 8.0 Hz). — 483

¹H-NMR (CDCl₃) δ ppm: 1.44 (3H, t, 7.0 Hz), 2.01-2.12 (2H, m), 2.63 (2H, t, J = 7.5 Hz), 2.67-2.81 (4H, m), 3.12-3.29 (4H, m), 4.44-4.55 (4H, m), 6.90 (1H, d, J = 7.5 Hz), 7.27 (1H, dd, J = 5.5 Hz, 7.5 Hz), 7.40 (2H, dd, J = 5.5 Hz, 8.0 Hz), 7.44 (1H, d, J = 1.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 8.90 (1H, d, J = 1.0 Hz) — 484

¹H-NMR (DMSO-d₆) δ ppm: 1.83-2.00 (2H, m), 2.59-2.70 (4H, m), 3.00-3.15 (4H, m), 3.17 (1H, d, J = 4.5 Hz), 3.31 (1H, d, J = 4.5 Hz), 4.15 (2H, t, J = 6.0 Hz), 4.77 (2H, q, J = 8.8 Hz), 6.90 (1H, d, J = 7.3 Hz), 7.27 (1H, t, J = 7.8 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 5.5 Hz). —

TABLE 71

Ex- ample R1 R2 R3 R4 R5 NMR Salt 485 —H —H —(CH₂)₂N(CH₃)CO₂C(CH₃)₃ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.43 (9H, s), 1.97-2.07 — (2H, m), 2.64 (2H, t, J = 7.5 Hz), 2.69-2.87 (6H, m), 2.81 (3H, s), 3.15-3.27 (4H, m), 3.38 (2H, t, J = 7.5 Hz), 4.04 (2H, t, J = 6.3 Hz), 6.83-6.92 (3H, m), 7.02-7.15 (2H, m), 7.28 (1H, t, J = 7.8 Hz), 7.37-7.43 (2H, m), 7.55 (1H, d, J = 8.0 Hz) 486 —H —H

—H —H ¹H-NMR (CDCl₃) δ ppm: 1.60-2.10 (6H, m), 2.30-2.40 (2H, m), 2.47 (3H, s), 2.60-2.70 (1H, m), 2.74 (4H, br), 2.85-3.00 (2H, m), 3.20 (4H, br), 3.90-4.10 (4H, m), 6.85-6.95 (2H, m), 7.07 (1H, d, J = 8.6 Hz), 7.25-7.45 (3H, m), 7.56 (1H, d, J = 8.0 Hz), 7.69 (2H, d, J = 8.2 Hz). — 487 —H —H —H —H —CO₂H ¹H-NMR (DMSO-d₆) δ ppm: 2.20-2.43 (2H, m), 3.17- — 3.77 (10H, m), 4.30 (2H, t, J = 6.0 Hz), 6.90-7.20 (2H, m), 7.30-7.40 (2H, m), 7.50-7.63 (1H, m), 7.70-7.79 (4H, m), 11.00 (1H, br), 12.71 (1H, br). 488 —OCH₃ —H —CO₂CH₃ —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.95-2.10 (2H, m), 2.31 (3H, — s), 2.60-2.80 (6H, m), 3.10-3.30 (4H, m), 3.89 (6H, s), 4.10 (2H, t, J = 6.4 Hz), 6.90 (1H, dd, J = 0.5, 7.6 Hz), 7.27 (1H, dd, J = 7.8, 7.8 Hz), 7.35-7.45 (3H, m), 7.50- 7.60 (2H, m). 489 —OCH —H —CO₂H —H —CH₃ ¹H-NMR (DMSO-d₆) δ ppm: 1.90-2.05 (2H, m), 2.26 — (3H, s), 2.55-3.30 (10H, m), 3.85 (3H, s), 4.03 (2H, t, J = 6.1 Hz), 6.93 (1H, d, J = 7.6 Hz), 7.29 (1H, dd, J = 7.8, 7.8 Hz), 7.35-7.50 (3H, m), 7.65 (1H, d, J = 8.0 Hz), 7.72 (1H, d, J = 5.5 Hz), 11.50-13.50 (1H, br).

TABLE 71-1

Example R1 R2 R3 R4 R5 NMR Salt 490 —CH₂CH═CH₂ —H —CO₂CH₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 1.98-2.09 (2H, m), 2.70-2.83 (6H, m), 3.13-3.30 (4H, — m), 3.45 (2H, d, J = 6.5 Hz), 3.89 (3H, s), 4.10 (2H, t, J = 6.4 Hz), 5.04-5.11 (2H, m), 5.91-6.09 (1H, m), 6.90 (1H, d, J = 7.5 Hz), 7.24-7.31 (1H, m), 7.38-7.44 (2H, m), 7.47-7.57 (3H, m). 491 —C₃H₇ —H —CO₂CH₃ —H —OCH₃ ¹H-NMR (CDCl₃) δ ppm: 0.97 (3H, t, J = 7.3 Hz), 1.52-1.74 (2H, m), 1.93- — 2.13 (2H, m), 2.57-2.85 (6H, m), 3.07-3.30 (4H, m), 3.89 (6H, s), 4.09 (2H, t, J = 6.3 Hz), 6.90 (1H, d, J = 7.5 Hz), 7.24-7.31 (1H, m), 7.38-7.45 (3H, m), 7.52- 7.57 (2H, m).

TABLE 72

Crystal form Example R1 n (Recrystallization solvent) Melting point(° C.) Salt 492

3 White powder (Ethyl acetate) 129.0-138.5 Hydrochloride 493

3 White powder (Ethyl acetate) 130.0-136.0 Hydrochloride 494

3 White powder Fumarate 495

4 White powder (Acetonitrile) 154-156 Dihydrochloride

TABLE 73

Crystal form Example R1 n (Recrystallization solvent) Melting point(° C.) Salt 496

3 White powder (Ethyl acetate) 151.5-156.5 Hydrochloride 497

4 White powder (Ethanol/ethyl acetate) 220-225 Dihydrochloride

TABLE 74

Ex- am- MS ple R1 R2 (M + 1) 498 —H -cyclo-C₆H₁₁ 478 499 —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ 508 500 —CH₂CH₂OH —CH₂CH₂OH 484 501 —CH₃ —CH₂CH₂N(CH₃)₂ 481 502 —CH₂CH₂OCH₃ —CH₂CH₂OCH₃ 512 503 —C₃H₇ —CH₂-cyclo-C₃H₅ 492 504 —CH₂CH═CH₂ -cyclo-C₅H₉ 504 505 —C₂H₅ —C₂H₅ 452 506 —H —C₄H₉ 452 507 —H —C(CH₃)₃ 452 508 —H -cyclo-C₇H₁₃ 492 509 —C₂H₅ -cyclo-C₆H₁₁ 506 510 —C₂H₅ —CH(CH₃)₂ 466 511 —H —CH₂CH(CH₃)₂ 452 512 —H —CH₂CH₂OCH₃ 454 513 —H —CH₂CH₂OC₂H₅ 468 514 —H —(CH₂)₃OC₂H₅ 482 515 —H -1-CH₃-CYCLOHEXYL 492 516 —H —CH₂-cyclo-C₃H₅ 450 517 —H —CH₂-cyclo-C₆H₁₁ 492 518 —H —CH₂CO₂CH₃ 468 519 —H —C H₂CONH₂ 453 520 —CH₃ —CH₂CO₂CH₃ 482 521 —H —CH₂CCH 434 522 —CH₃ —CH(CH₃)₂ 452 523 —H —(CH₂)₂CH(CH₃)₂ 466 524 —H —CH(CH₃)C(CH₃)₃ 480 525 —H —CH₂CH₂N(CH₃)₂ 467 526 —CH₃ —CH₂-cyclo-C₃H₅ 464 527 —H —CH₂CF₃ 478 528 —CH₃ -cyclo-C₆H₁₁ 492 529 —C₂H₅ —CH₂CH₂OH 468 530 —CH₂CH₂OH -cyclo-C₆H₁₁ 522 531 —H -cyclo-C₅H₉ 464 532 —H -3-PYRIDYL 473 533 —H -4-PYRIDYL 473 534 —CH₂CH₂OH —C₆H₅ 516

TABLE 75

Exam- MS ple R1 R2 (M + 1) 535 —H —C₆H₅ 435 536 —H —CH₂CH₂C(CH₃)₃ 468 537 —H —CH(C₂H₅)₂ 449 538 —H —CH₂CN 566 539 —H —(CH₂)₃OCH₃ 523 540 —H —CH₂CH₂CN 523 541 —(CH₂)₃N(CH₃)₂ —(CH₂)₃N(CH₃)₂ 481 542 —CH₃ —(CH₂)₃N(C₂H₅)₂ 482 543 —C₂H₅ —(CH₂)₂N(C₂H₅)₂ 523 544 —H —(CH₂)₂NHCOCH₃ 481 545 —H —(CH₂)₅OH 495 546 —H —(CH₂)₂N(I—Pr)₂ 524 547 —H —(CH₂)₃N(CH₃)₂ 524 548 —H —(CH₂)₂N(C₂H₅)₂ 563 549 —CH₃ —(CH₂)₃CO₂C₂H₅ 509 550 —H —(CH₂)₄CO₂C₂H₅ 493 551 -cyclo-C₅H₉ —(CH₂)₂N(C₂H₅)₂ 528 552 —CH₃ —(CH₂)₂N(C₂H₅)₂ 484 553 —H —NHCH₂CF₃ 496 554 —H —CH₂CF₂CF₃ 482 555 —H —CH₂CH(OCH₃)₂ 442 556 —H —(CH₂)₃OCH(CH₃)₂ 467 557 —H —(CH₂)₂OCH(CH₃)₂ 470 558 —H —CH₂CH₂F 435 559 —H —CH₂CONHCH₃ 468 560 —H —CH₂CH₂SCH₃ 449

TABLE 76

Example R1 R2 MS (M + 1) 561 —H

510 562 —H

524 563 —H

495 564 —H

496 565 —H

482 566 —H

467 567 —H

466 568 —H

480 569 —H

568 570 —H

554

TABLE 77

Exam- MS ple R1 R2 (M + 1) 571 —H

496 572 —H

482 573 —H

468 574 —H

470 575 —H

450 576 —H

509 577 —H

481 578 —H

450 579 —H

478

TABLE 78

Exam- MS ple R1 R2 (M + 1) 580 —H

494 581 —H

492 582 —H

536 583 —CH₃

516 584 —CH₃

520 585 —H

551 586 —H

506 587 —H

502 588 —H

502 589 —H

502

TABLE 79

Exam- MS ple R1 R2 (M + 1) 590 —H

506 591 —H

506 592 —H

540 593 —H

554 594 —H

554 595 —H

487 596 —H

533 597 —CH₃

515 598 —H

487

TABLE 80

Ex- MS am- (M + ple R1 R2 1) 599 —H

487 600 —H

487 601 —C₂H₃

529 602 —C₂H₅

515 603 —H

501 604 —H

501 605 —H

501 606 —CH₃

507 607 —CH₃

535 608 —H

535

TABLE 81

Exam- MS ple R1 R2 (M + 1) 609 —H

551 610 —H

579 611 —H

479 612 —H

493 613 —H

507 614 —H

565 615 —H

465 616 —H

479 617 —H

493 618 —H

507

TABLE 82

Exam- MS ple R1 R2 (M + 1) 619 —H

507 620 —H

521 621 —H

507 622 —H

536 623 —H

507 624 —H

509 625 —H

523 626 —H

476 627 —H

490 628 —H

504

TABLE 83

Exam- MS ple R1 R2 (M + 1) 629 —H

476 630 —H

480 631 —H

480 632 —C₂H₅

522 633 —H

494 634 —H

482 635 —H

496 636 —H

492 637 —H

506 638 —H

492

TABLE 84

Exam- MS ple R1 R2 (M + 1) 639 —H

506 640 —H

489 641 —H

503 642 —H

489 643 —H

490 644 —H

538 645 —H

528 646 —H

518 647 —H

518 648 —H

504

TABLE 85

Exam- MS ple R1 R2 (M + 1) 649 —H

520 650 —H

504 651 —H

533 652 —H

490 653 —H

479 654 —H

494 655 —H

491 656 —H

502 657 —H

526 658 —H

533

TABLE 86

Exam- MS ple R1 R2 (M + 1) 659 —H

512 660 —H

511 661 —H

539 662 —H

528 663 —H

523 664 —H

523 665 —H

555 666 —H

571 667 —H

555 668 —H

570

TABLE 87

Example R1 MS (M + 1) 669 —H 465 670 —C₄H₉ 521 671 —CH(C₂H₅)₂ 535 672 —CH(CH₃)₂ 507 673 —C(CH₃)₃ 535 674 —C₃H₇ 507 675 —C₂H₅ 493 676 —C₆H₁₃ 549 677 -cyclo-C₅H₉ 533 678 -cyclo-C₇H₁₃ 561 679 —CH₂CH₂OH 509 680 —CH₂CH₂OCH₃ 523 681 —(CH₂)₃OCH₃ 537 682 —(CH₂)₄OCH₃ 551 683 —CO₂C₂H₅ 537 684 —CO₂C(CH₃)₃ 565 685 —COCH₃ 507 686 —(CH₂)₃N(CH₃)₂ 550 687 —CH₂CH₂N(CH₃)₂ 536

TABLE 88

Example R1 MS (M + 1) 688

576 689

578 690

562 691

551 692

565 693

549 694

576 695

576 696

576 697

556 698

556

TABLE 89

Example R1 MS (M + 1) 699

556 700

570 701

570 702

632 703

559 704

545 705

561 706 -4-PYRIDYL 542 707 -3-PYRIDYL 542 708 -2-PYRIDYL 542 709

567 710

556 711

556

TABLE 90

Example R1 MS (M + 1) 712

610 713

598

TABLE 91

MS Example R1 (M + 1) 714

450 715

480 716

493 717

466 718

507 719

549 720

507 721

533 722

547 723

562 724

535

TABLE 92

MS Example R1 (M + 1) 725

464 726

492 727

480 728

480 729

494 730

494 731

549 732

507 733

494 734

564

TABLE 93

MS Example R1 (M + 1) 735

536 736

536 737

536 738

521 739

579 740

547 741

576 742

562 743

549 744

576 745

522

TABLE 94

Exam- MS ple R1 (M + 1) 746

478 747

482 748

494 749

563 750

479 751

493 752

556 753

476 754

468 755

504

TABLE 95

MS Example R1 (M + 1) 756

600 757

498 758

512 759

551

TABLE 96

MS Example R1 R2 (M + 1) 760 —H -cyclo-C₆H₁₁ 522 761 —H —CH(CH₃)₂ 482 762 —H —C₄H₉ 496 763 —H -cyclo-C₃H₅ 480 764 —H -cyclo-C₇H₁₃ 536 765 —H —CH₂C₆H₅ 530 766 —H —C₃H₇ 482 767 —H —CH₂CH(CH₃)₂ 496 768 —H —CH₂CH₂OCH₃ 498 769 —H —CH₂CH₂OC₂H₅ 512 770 —H —(CH₂)₃OC₂H₅ 526 771 —H -1-CH3-CYCLOHEXYL 536 772 —H —(CH₂)₂OC₆H₅ 560 773 —H -cyclo-C₅H₉ 508 774 —H —CH₂-cyclo-C₃H₅ 494 775 —H —CH₂-cyclo-C₆H₁₁ 536 776 —H —CH(CH₃)C₆H₅ 544 777 —H —(CH₂)₂C₆H₅ 544 778 —H —CH₂CO₂CH₃ 512 779 —H —CH₂CONH₂ 497 780 —H —CH₂CCH 478 781 —H —(CH₂)₂CH(CH₃)₂ 510 782 —H —CH(CH₃)C(CH₃)₃ 524 783 —H —CH₂C(CH₃)₃ 510 784 —CH₃ -cyclo-C₆H₁₁ 536 785 —C₂H₅ —C₂H₅ 496 786 —H —C(CH₃)₃ 496 787 —CH₃ —CH₂C₆H₅ 544 788 —C₂H₅ —CH(CH₃)₂ 510 789 —CH₃ —CH₂CO₂CH₃ 526 790 —CH₃ —CH(CH₃)₂ 496 791 —CH₃ —CH₂-cyclo-C₃H₅ 508 792 —H —CH₂CF₃ 522 793 —H —CH(C₂H₅)₂ 510

TABLE 97

Example R1 R2 MS (M + 1) 794 —H —(CH₂)₃OCH₃ 512 795 —H —CH₂CH₂OH 484 796 —H —CH₂CN 479 797 —C₂H₅ -2-PYRIDYL 545 798 —H -3-PYRIDYL 517 799 —H —C₆H₅ 516 800 —H —(CH₂)₂NHCOCH₃ 525 801 —H —CH₂CH(C₂H₅)₂ 524 802 —H —CH₂CH(OCH₃)₂ 528 803 —H —(CH₂)₃OCH(CH₃)₂ 540 804 —H —(CH₂)₂OCH(CH₃)₂ 526 805 —H —CH₂CH₂F 486 806 —H —CH₂CONHCH₃ 511 807 —H —CH₂CH₂SCH₃ 514 808 —H —CH₂CHF₂ 504

TABLE 98

MS Example R1 R2 (M + 1) 809 —H

554 810 —H

568 811 —H

539 812 —H

598 813 —H

540 814 —H

526 815 —H

511 816 —H

494 817 —H

540 818 —H

612 819 —C₂H₅

522

TABLE 99

MS Example R1 R2 (M + 1) 820 —H

526 821 —H

512 822 —H

514 823 —H

496 824 —H

494 825 —H

522 826 —H

538 827 —H

536 828 —H

580 829 —CH₃

560 830 —CH₃

544

TABLE 100

Exam- MS ple R1 R2 (M + 1) 831 —CH₃

564 832 —H

562 833 —H

562 834 —H

584 835 —H

600 836 —H

572 837 —H

550 838 —H

546 839 —H

546 840 —H

546 841 —H

550

TABLE 101

MS Example R1 R2 (M + 1) 842 —H

550 843 —H

530 844 —H

558 845 —H

574 846 —H

576 847 —H

592 848 —H

581 849 —H

580 850 —H

576 851 —H

576

TABLE 102

Exam- MS ple R1 R2 (M + 1) 852 —H

560 853 —H

603 854 —H

576 855 —H

556 856 —H

558 857 —H

564 858 —H

564 859 —H

564 860 —H

572 861 —H

560 862 —H

560

TABLE 103

Example R1 R2 MS (M + 1) 863 —H

574 864 —H

574 865 —H

578 866 —H

598 867 —H

614 868 —H

574 869 —H

548 870 —H

590 871 —H

544 872 —H

562 873 —H

602

TABLE 104

Example R1 R2 MS (M + 1) 874 —H

588 875 —H

587 876 —H

560 877 —H

562 878 —H

574 879 —H

578 880 —H

558 881 —H

558 882 —H

578 883 —H

562

TABLE 105

Example R1 R2 MS (M + 1) 884 —H

590 885 —H

574 886 —H

630 887 —CH₃

558 888 —CH₃

588 889 —CH₃

574 890 —H

598 891 —H

548 892 —H

598 893 —H

548

TABLE 106

Example R1 R2 MS (M + 1) 894 —H

566 895 —H

614 896 —H

562 897 —H

562 898 —H

562 899 —H

580 900 —H

612 901 —H

612 902 —H

612

TABLE 107

Example R1 R2 MS (M + 1) 903 —H

576 904 —H

576 905 —H

576 906 —H

594 907 —H

626 908 —H

626 909 —H

626 910 —H

566 911 —H

628

TABLE 108

Example R1 R2 MS (M + 1) 912 —H

602 913 —H

606 914 —C₂H₅

584 915 —H

566 916 —H

580 917 —H

531 918 —H

531 919 —H

531 920 —H

545 921 —C₂H₅

573

TABLE 109

Example R1 R2 MS (M + 1) 922 —C₂H₅

559 923 —H

545 924 —H

545 925 —H

579 926 —CH₃

675 927 —H

565 928 —H

551 929 —H

520 930 —H

534 931 —H

548

TABLE 110

Example R1 R2 MS (M + 1) 932 —H

520 933 —H

524 934 —H

524 935 —H

538 936 —H

526 937 —H

540 938 —H

536 939 —H

550 940 —H

536 941 —H

550

TABLE 111

Example R1 R2 MS (M + 1) 942 —H

533 943 —H

533 944 —H

562 945 —H

548 946 —H

548 947 —H

577 948 —H

592 949 —H

534 950 —H

537 951 —H

546 952 —H

556

TABLE 112

Example R1 R2 MS (M + 1) 953 —H

583 954 —H

598 955 —H

570 956 —H

572 957 —H

599 958 —H

615 959 —H

598

TABLE 113

Example R1 R2 R3 R4 R5 MS (M + 1) 960 —H —H —NHCOCH₃ —H —H 410 961 —H —NHCOCH₃ —H —H —H 410 962 —H —H —OCH₃ —H —H 383 963 —H —H —Cl —H —H 387 964 —H —H —CH₃ —H —H 367 965 —H —H —CF₃ —H —H 421 966 —H —H —OCF₃ —H —H 437 967 —H —H —SCH₃ —H —H 399 968 —H —H —C₆H₅ —H —H 429 969 —H —H —OCH₂C₆H₅ —H —H 459 970 —H —H —NO₂ —H —H 398 971 —H —H —COCH₃ —H —H 395 972 —OCH₃ —OCH₃ —H —H —H 413 973 —OCH₃ —H —H —H —OCH₃ 413 974 —H —OCH₃ —OCH₃ —H —H 413 975 —H —CH₃ —H —H —H 367 976 —CH₃ —H —H —H —CH₃ 381 977 —F —H —H —H —H 371 978 —H —F —H —H —H 371 979 —H —H —F —H —H 371 980 —F —H —F —H —H 389 981 —H —F —H —H —F 389 982 —F —H —H —H —F 389 983 —F —H —H —CH₃ —H 385 984 —H —H —CH₂CO₂CH₃ —H —H 425 985 —CH₃ —H —COCH₃ —H —H 409 986 —H —C₆H₅ —H —H —H 445 987

—H —H —H —H 420 988 —H —H

—H —H 419

TABLE 114

Example R1 MS (M + 1) 989 -3-PYRIDYL 354 990

368 991

385 992

407 993

393 994

407 995

407 996

421 997

421 998

419 999

419 1000 

428

TABLE 115

Example R1 MS (M + 1) 1001

433 1002

433 1003

437 1004

409 1005

423 1006

409 1007

421 1008

435 1009

451 1010

427 1011

394

TABLE 116

Example R1 MS (M + 1) 1012

395 1013

450 1014

436 1015

410 1016

424 1017

424 1018 -2-BENZTHIAZOLYL 410 1019

438 1020

440 1021

451 1022

465

TABLE 117

Example R1 MS (M + 1) 1023

465 1024

436 1025

450 1026

436 1027

438 1028

452 1029

438 1030

438 1031

479 1032

451

TABLE 118

Example R1 MS (M + 1) 1033

465 1034

479 1035

450 1036

443

TABLE 119

Example R1 MS (M + 1) 1037

464 1038

450 1039

424 1040

438 1041

438 1042

452 1043

454 1044

479 1045

465

TABLE 120

Example R1 MS (M + 1) 1046

479 1047

450 1048

464 1049

450 1050

466 1051

465 1052

493 1053

479 1054

493 1055

464

TABLE 121

Crystal form Melting point Example R1 R2 R3 R4 R5 (Recrystallization solvent) (° C.) salt 1056 —OCH₃ —H —NHSO₂C₂H₅ —H —CH₃ White powder 235.5-237.5 Hydrochloride (Ethyl acetate) 1057 —CH₃ —H —CONHCH₃ —H —OH White powder 246.5 Hydrochloride (Ethyl acetate) (dec) 1058 —CH₃ —H —Br —H —OCH₃ White powder 265.0 Hydrochloride (Ethanol/ethyl acetate) (dec) 1059 —OCH₃ —H —NHCOCH₂NHCO₂C(CH₃)₃ —H —CH₃ White powder 140.5-142.5 — (Ethyl acetate/isopropyl ether) 1060 —CH₃ —H —NHCOCH₂NH₂ —H —OCH₃ White powder 268.0 Dihydrochloride (Methanol/water) (dec) 1061 —OCH₃ —H —NHCOCH₂NHCOCH₃ —H —CH₃ White powder 167.5-170.5 — (Ethyl acetate/isopropyl ether) 1062 —OCH₃ —H —NHCOCH₂NHCO₂CH₃ —H —CH₃ White powder 157.0-159.5 — (Ethyl acetate/isopropyl ether) 1063 —CH₃ —H —NHCOCH₂NHCHO —H —OCH₃ White powder 235.5 Hydrochloride (Dichloromethane/water) (dec)

TABLE 122

Crystal form Melting point Example R1 R2 R3 R4 R5 (Recrystallization solvent) (° C.) salt 1064 —CH₃ —H —CONHCH₃ —H —O(CH₂)₂N(CH₃)₂ White powder 235.5-240.5 Dihydrochloride (Ethyl acetate) (dec) 1065 —CH₃ —H —CONHCH₃ —H —O(CH₂)₂OCH₃ White powder 194.0-197.5 Hydrochloride (Isopropyl alcohol/isopropyl ether) 1066 —CH₃ —H —CONHCH₃ —H —OCH₂CF₃ Light yellow powder 156.0-157.5 Hydrochloride (Ethyl acetate/isopropyl ether)

TABLE 123

Crystal form Melting point Example R1 R2 R3 R4 R5 (Recrystallization solvent) (° C.) Salt 1067 —H —H

—H —H White powder (Ethyl acetate/isopropyl ether) 114.0-115.5 — 1068 —OCH₃ —H

—H —CH₃ White powder (Ethanol/ethyl acetate) 245.0 (dec) Hydrochloride 1069 —H —H

—H —H White powder (Ethyl acetate) 217.0-224.5 (dec) Hydrochloride 1070 —OCH₃ —H

—H —CHO White powder (Ethanol) 218.0 (dec) Hydrochloride 1071 —OCH₃ —H

—H —CH₂OH White powder (Ethanol) 224.0-226.5 (dec) Hydrochloride 1072 —OCH₃ —H

—H —CH₂OCH₃ White powder (Ethanol) 224.0-226.0 Hydrochloride

TABLE 124

Crystal form Melting point Example R1 R2 R3 R4 R5 (Recrystallization solvent) (° C.) Salt 1073 —OCH₃ —H

—H —CH₂N(CH₃)₂ White powder (Ethanol/ether) 151.0-152.0 Difumarate 1074 —OCH₃ —H

—H —CH₃ Light yellow powder (Ethanol/water) 264.0 (dec) Hydrochloride 1075 —OCH₃ —H

—H —CH₃ Light yellow powder (Ethyl acetate/isopropyl ether) 143.5-151.0 — 1076 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 246.5-249.0 (dec) Hydrochloride 1077 —OCH₃ —H

—H —CH₃ Light yellow powder (Ethyl acetate) 234.0-240.0 (dec) Dihydrochloride 1078 —OCH₃ —H

—H —CH₃ White powder (Methanol/water) 286.5 (dec) Dihydrochloride

TABLE 125

Crystal form Melting point Example R1 R2 R3 R4 R5 (Recrystallization solvent) (° C.) Salt 1079 —OCH₃ —H

—H —CH₃ White powder (Ethanol/water) 218.0-221.5 Hydrochloride 1080 —OCH₃ —H

—H —CH₃ White powder (Ethanol/ethyl acetate) 223.0-228.0 Hydrochloride 1081 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate/isopropyl ether) 139.5-142.0 — 1082 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 270.0 (dec) Trihydrochloride 1083 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 257.0-261.0 (dec) Hydrochloride 1084 —OCH₃ —H

—H —CH₂OH White powder (Ethyl acetate) 217.5-221.0 Hydrochloride

TABLE 126

Crystal form Melting point Example R1 R2 R3 R4 R5 (Recrystallization solvent) (° C.) Salt 1085 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 250.0 (dec) Hydrochloride 1086 —OCH₃ —H

—H —CHO Light yellow powder (Ethyl acetate) 225.0 (dec) Hydrochloride 1087 —OCH₃ —H

—H —CH₂OH White powder (Ethyl acetate/isopropyl ether) 128.0-130.0 — 1088 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 246.0 (dec) Hydrochloride 1089 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 248.0-251.0 (dec) Dihydrochloride

TABLE 127

Example R1 R2 R3 R4 R5 NMR Salt 1090 —NH₂ —H —CONHC₂H₅ —H —H ¹H-NMR (CDCl₃) δ ppm: 1.23 (3H, t, J = 7.4 Hz), 2.00-2.15 (2H, m), — 2.67 (2H, t, J = 7.3 Hz), 2.75 (4H, brs), 3.21 (4H, brs), 3.40- 3.50 (2H, m), 3.50-4.30 (2H, br), 4.13 (2H, t, J = 6.5 Hz), 5.99 (1H, brs), 6.80 (1H, d, J = 8.4 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.08 (1H, dd, J = 2.1, 8.3 Hz), 7.19 (1H, d, J = 2.1 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz).

TABLE 128

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 1091

White powder (Ethanol/ethyl acetate) 166.0-171.0 — 1092

White powder (Ethyl acetate/isopropyl ether) 138.5-141.0 —

TABLE 129

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 1093

White powder (Ethyl acetate/isopropyl ether) 138.5-140.5 — 1094

White powder (Ethanol) 233.5 (dec) Hydrochloride 1095

White powder (Ethyl acetate/isopropyl ether) 147.0-148.5 — 1096

White powder (water) 115.0-121.0 — 1097

White powder (Ethyl acetate/isopropyl ether) 129.0-130.5 — 1098

White powder (Ethyl acetate/isopropyl ether) 139.0-140.5 —

TABLE 130

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 1099

White powder (Ethyl acetate/isopropyl ether) 128.5-131.5 — 1100

White powder (Isopropyl alcohol/ethyl acetate) 227.0 (dec) Hydrochloride 1101

White powder (Ethanol/ethyl acetate) 211.0-213.5 Hydrochloride 1102

White powder (Ethanol/water) 245.0 (dec) Hydrochloride 1103

White powder (Ethyl acetate/isopropyl ether) 112.0-113.0 — 1104

White powder (Ethyl acetate/isopropyl ether) 123.5-126.0 — 1105

Light yellow powder (Ethyl acetate) 174.0-176.5 Hydrochloride 1106

White powder (Ethyl acetate/isopropyl ether) 137.0-139.0 —

TABLE 131

Crystal form Melting point Example R1 (Recrystallization solvent) (° C.) Salt 1107

White powder (Ethyl acetate) 194.0-196.0 Hydrochloride 1108

White powder (Ethyl acetate) 173.0-177.0 Dihydrochloride 1109

White powder (Ethyl acetate/isopropyl ether) 162.5-165.0 — 1110

White powder (Methanol) 202-205 Hydrochloride 1111

White powder (Methanol) 208-210 Hydrochloride 1112

White powder (Ethanol) 255.0-257.0 Hydrochloride 1113

White powder (Methanol) 178-182 Hydrochloride

TABLE 132

Crystal form (Recrystalization Melting point Example R1 solvent) (° C.) Salt 1114

White powder (Ethyl acetate) 199.0-201.5 Hydrochloride 1115

White powder (Ethyl acetate/ isopropyl ether) 107.5-108.5 — 1116

White powder (Ethyl acetate/ isopropyl ether) 110.0-112.0 — 1117

White powder (water) 203.0-210.0 — 1118

White powder (Ethyl acetate/ isopropyl ether) 167.0-169.0 — 1119

White powder (Ethyl acetate) 138.0-140.0 — 1120

White powder (Ethyl acetate/hexane) 115   — 1121

Light brown powder (Ethanol) 134.7 —

TABLE 133

Crystal form (Recrystalization Melting point Example R1 solvent) (° C.) Salt 1122

White powder (Ethanol) 131.3 — 1123

White powder (Ethanol) 107.1 — 1124

White powder (Ethyl acetate) 231.3-232.8 Hydrochloride 1125

White powder (Ethyl acetate) 218.9-221.0 Hydrochloride 1126

White powder (Ethyl acetate) 259.0-260.2 Hydrochloride

TABLE 134

Example R1 Melting point (° C.) Salt 1127

¹H-NMR (DMSO-d₆) δ ppm:: 1.80-2.10 (4H, m), 2.74 (6H, s), 3.10-3.70 (16H, m), 4.00-4.10 (1H, m), 6.97 (1H, d, J = 7.5 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.49 (1H, d, J = 5.6 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 10.91 (1H, brs). Hydrochloride 1128

¹H-NMR (DMSO-d₆) δ ppm: 1.80-2.10 (4H, m), 1.93 (3H, s), 3.10-3.60 (16H, m), 3.90-4.10 (1H, m), 6.95 (1H, d, J = 7.5 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.47 (1H, d, J = 5.5 Hz), 7.68 (1H, d, J = 8.0 Hz), 7.75 (1H, d, J = 5.5 Hz), 11.30 (1H, brs). Hydrochloride 1129

¹H-NMR (DMSO-d₆) δ ppm: 2.20-2.40 (2H, m), 2.70-3.70 (10H, m), 4.55 (2H, t, J = 5.9 Hz), 6.98 (1H, d, J = 7.5 Hz), 7.32 (1H, t, J = 7.9 Hz), 7.50 (1H, d, J = 5.5 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.77 (1H, d, J = 5.5 Hz), 7.89 (1H, s), 10.97 (1H, brs), 12.93 (1H, brs). Hydrochloride 1130

¹H-NMR (DMSO-d₆) δ ppm: 2.25-2.35 (2H, m), 3.20-4.00 (10H, m), 4.30 (2H, t, J = 5.8 Hz), 6.97 (1H, d, J = 7.5 Hz), 7.24 (1H, dd, J = 5.5, 2.8 Hz), 7.31 (1H, t, J = 7.8 Hz), 7.49 (1H, d, J = 5.4 Hz), 7.59 (1H, d, J = 2.5 Hz), 7.70 (1H, d, J = 8.1 Hz), 7.76 (1H, d, J = 5.5 Hz), 8.53 (1H, d, J = 5.7 Hz), 10.99 (1H, brs). Hydrochloride 1131

¹H-NMR (CDCl₃) δ ppm: 1.89-2.13 (2H, m), 2.52-2.83 (6H, m), 3.03-3.3- (4H, m), 4.01 (2H, t, J = 6.3 Hz), 4.46 (2H, brs), 5.30 (1H, brs), 6.51 (1H, dd, J = 8.3, 2.3 Hz), 6.83-6.96 (2H, m), 7.19-7.45 (3H, m), 7.48 (1H, brs), 7.55 (1H, d, J = 8.0 Hz). fumarate

TABLE 135

Crystal form (Recrystalization Melting point Example R1 solvent) (° C.) Salt 1132

Light brown powder (Ethanol/ethyl acetate) 103.5-106.0 — 1133

Light brown powder (Dichloromethane/water) 140.5-144.0 — 1134

White powder (Ethyl acetate/ isopropyl ether) 143.0-144.5 — 1135

White powder (Ethanol/ethyl acetate) 211.0-213.5 Hydrochloride 1136

White powder (Ethyl acetate) 207.5-209.5 Hydrochloride 1137

White powder (Ethanol) 167.0-168.5 Hydrochloride 1138

White powder (Ethyl acetate) 156.5-158.5 Hydrochloride 1139

White powder (Ethyl acetate/ isopropyl ether) 157.5-161.5 —

TABLE 136

Crystal form (Recrystalization Melting point Example R1 solvent) (° C.) Salt 1140

White powder (Ethyl acetate) 203.5-206.0 Hydrochloride 1141

White powder (Ethyl acetate) 186.0-187.5 Hydrochloride 1142

White powder (Ethyl acetate) 203.0-207.0 Hydrochloride 1143

White powder (Ethyl acetate/ isopropyl ether) 146.5-148.0 — 1144

White powder (Ethyl acetate/ isopropyl ether) 96.5-97.0 — 1145

White powder (acetic acid) 254.0 (dec) Dihydrochloride 1146

White powder (Ethyl acetate/ isopropyl ether) 124.0-126.5 — 1147

White powder (Ethanol/ethyl acetate) 181.5-183.5 — 1148

White powder (Ethyl acetate) 230.2-231.5 Hydrochloride 1149

White powder (Ethyl acetate) 207.4-209.6 Hydrochloride

TABLE 137

Crystal form (Recrystalization Melting point Example R1 solvent) (° C.) Salt 1150

White powder (Ethyl acetate) 213.8-215.2 Hydrochloride 1151

White powder (Ethyl acetate) 217.0-218.0 Hydrochloride 1152

White powder (Ethyl acetate) 231.6-232.9 Hydrochloride 1153

Light yellow powder (Ethanol) 135.7 — 1154

Light brown powder (Ethanol) 238.1-240.1 Hydrochloride 1155

White powder (Ethanol) 210.4 Hydrochloride 1156

White powder (Ethanol)  94.1 —

TABLE 138

Example R1 NMR Salt 1157

¹H-NMR (CDCl₃) δ ppm: 1.72-1.83 (2H, m), 1.83- 1.98 (2H, m), 2.48-2.59 (2H, m), 2.64-2.81 (4H, m), 3.12-3.28 (4H, m), 3.46 (3H, s), 3.58 (3H, s), 4.13 (2H, t, J = 6.3 Hz), 6.62 (1H, d, J = 2.1 Hz), 6.80 (1H, dd, J = 8.8, 2.1 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.20-7.31 (1H, m), 7.35- 7.43 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 8.15 (1H, d, J = 8.8 Hz). —

TABLE 139

Crystal form (Recrystalization Melting point Example R1 solvent) (° C.) Salt 1158

White powder (Ethyl acetate) 200.5-201.5 Hydrochloride 1159

White powder (Ethanol/ethyl acetate) 225.0-230.0 Hydrochloride 1160

White powder (Dichloromethane/water) 156.0-158.5 — 1161

White powder (Ethanol/ethyl acetate) 169.0-171.5 —

TABLE 140

Example R1 R2 R3 R4 R5 NMR 1162 —OCH₃ —H —NHCO2C(CH₃)₃ —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.51 (9H, s), 1.95-2.10 (2H, m), 2.24 (3H, s), 2.66- 2.81 (6H, m), 3.14-3.31 (2H, m), 3.84 (3H, s), 3.95 (2H, t, J = 6.3 Hz), 6.36 (1H, br), 6.60 (1H, d, J = 2.5 Hz), 6.87-6.92 (1H, m), 7.01 (1H, d, J = 2.0 Hz), 7.24-7.31 (1H, m), 7.37-7.44 (2H, m), 7.55 (1H, d, J = 8.0 Hz) 1163 —OCH₃ —H —I —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.92-2.10 (2H, m), 2.23 (3H, s), 2.57-2.86 (6H, m), 3.11-3.31 (4H, m), 3.82 (3H, s), 3.98 (2H, t, J = 6.4 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.03 (1H, d, J = 2.0 Hz), 7.13 (1H, d, J = 1.6 Hz), 7.22-7.34 (1H, m), 7.40 (1H, dd, J = 5.5 Hz, 9.3 Hz), 7.55 (1H, d, J = 8.0 Hz). 1164 —OCH₃ —H —NHCONH(CH₂)₂Cl —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.94-2.13 (2H, m), 2.26 (3H, s), 2.60-2.90 (6H, m), 3.12-3.33 (4H, m), 3.49-3.75 (4H, m), 3.83 (3H, s), 3.97 (2H, t, J = 6.4 Hz), 5.22 (1H, br), 6.25 (1H, br), 6.59 (1H, d, J = 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 6.91 (1H, d, J = 7.4 Hz), 7.21-7.33 (1H, m), 7.41 (1H, dd, J = 5.6 Hz, 7.6 Hz), 7.56 (1H, d, J = 8.0 Hz). 1165 —OCH₃ —H —NH(CH₂)₂NH₂ —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.91-2.08 (2H, m), 2.22 (3H, s), 2.62-2.81 (6H, m), 2.95 (2H, t, J = 5.7 Hz), 3.08-3.27 (6H, m), 3.80 (3H, s), 3.91 (2H, t, J = 6.4 Hz), 6.05 (1H, d, J = 2.6 Hz), 6.10 (1H, d, J = 2.6 Hz), 6.90 (1H, d, J = 7.5 Hz), 7.20-7.32 (1H, m), 7.34-7.46 (2H, m), 7.55 (1H, d, J = 8.0 Hz). 1166 —OCH₃ —H —NH(CH₂)₂NHCOCH₂Cl —H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.91-2.11 (2H, m), 2.23 (3H, s), 2.60-2.84 (6H, m), 3.11-3.26 (4H, m), 3.26-3.36 (2H, m), 3.45-3.63 (2H, m), 3.81 (3H, s), 3.91 (2H, t, J = 6.4 Hz), 4.06 (2H, s), 6.04 (1H, d, J = 2.5 Hz), 6.10 (1H, d, J = 2.5 Hz), 6.78-6.96 (2H, m), 7.21-7.33 (1H, m), 7.35-7.47 (2H, m), 7.55 (1H, d, J = 8.1 Hz).

TABLE 141

Example R1 R2 R3 R4 R5 NMR 1167 —OCH₃ —H

—H —CH₂Cl ¹H-NMR (CDCl₃) δ ppm: 2.00-2.17 (2H, m), 2.63-2.83 (6H, m), 3.14-3.28 (2H, m), 3.89 (3H, s), 3.98-4.17 (4H, m), 4.40-4.54 (2H, m), 4.69 (2H, m), 6.77 (1H, d, J = 2.5 Hz), 6.91 (1H, d, J = 2.5 Hz), 7.21-7.32 (1H, m), 7.35-7.46 (2H, m), 7.55 (1H, d, J = 9.3 Hz) 1168 —OCH₃ —H

—H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.48 (9H, s), 1.93-2.12 (2H, m), 2.26 (3H, s), 2.60-2.86 (6H, m), 2.95-3.12 (4H, m), 3.14- 3.31 (4H, m), 3.50-3.67 (4H, m), 3.83 (3H, s), 3.94 (2H, t, J = 6.3 Hz), 6.33 (1H, d, J = 2.5 Hz), 6.38 (1H, d, J = 2.5 Hz), 6.90 (1H, d, J = 7.5 Hz), 7.19-7.33 (1H, m), 7.41 (2H, dd, J = 5.5 Hz, 9.3 Hz), 7.55 (1H, d, J = 8.0 Hz). 1169 —OCH₃ —H

—H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.92-2.09 (2H, m), 2.26 (3H, s), 2.61-2.81 (6H, m), 2.98-3.12 (8H, m), 3.14-3.25 (4H, m), 3.83 (3H, s), 3.94 (2H, t, J = 6.4 Hz), 6.33 (1H, d, J = 2.5 Hz), 6.38 (1H, d, J = 2.5 Hz), 6.90 (1H, d, J = 7.0 Hz), 7.20-7.33 (1H, m), 7.34-7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz). 1170 —OCH₃ —H

—H —CH₃ ¹H-NMR (CDCl₃) δ ppm: 1.50 (9H, s), 1.95-2.11 (2H, m), 2.27 (3H, s), 2.59-2.82 (6H, m), 3.12-3.27 (4H, m), 3.63- 3.81 (4H, m), 3.83 (3H, s), 4.01 (2H, t, J = 6.4 Hz), 4.24 (2H, s), 6.61-6.71 (2H, m), 6.90 (1H, d, J = 7.6 Hz), 7.21-7.33 (1H, m), 7.41 (2H, dd, J = 5.5 Hz, 9.8 Hz), 7.55 (1H, d, J = 8.1 Hz). 1171 —OCH₃ —H

—H —CHO ¹H-NMR (CDCl₃) δ ppm: 1.49 (9H, s), 1.96-2.12 (2H, m), 2.60-2.82 (6H, m), 3.04-3.16 (4H, m), 3.16-3.28 (4H, m), 3.52-3.64 (4H, m), 3.89 (3H, s), 4.14 (2H, t, J = 6.3 Hz), 6.78 (1H, d, J = 2.8 Hz), 6.86-6.96 (2H, m), 7.20-7.33 (1H, m), 7.35-7.46 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 10.44 (1H, s). 1172 —OCH₃ —H

—H —CHO ¹H-NMR (CDCl₃) δ ppm: 1.97-2.13 (2H, m), 2.59-2.83 (6H, m), 2.96-3.09 (4H, m), 3.09-3.17 (4H, m), 3.17- 3.28 (4H, m), 3.89 (3H, s), 4.13 (2H, t, J = 6.5 Hz), 6.79 (1H, d, J = 2.7 Hz), 6.86-6.96 (2H, m), 7.20-7.34 (1H, m), 7.36-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz), 10.44 (1H, s).

TABLE 142

Example R1 NMR 1173

¹H-NMR (CDCl₃) δ ppm: 2.70-2.87 (4H, m), 2.95 (2H, t, J = 5.1 Hz), 2.99-3.14 (4H, m), 4.42 (2H, t, J = 5.1 Hz), 6.78 (1H, dd, J = 0.6 Hz, 7.6 Hz), 7.18-7.30 (1H, m), 7.38 (2H, s), 7.54 (1H, d, J = 8.0 Hz), 7.69-7.80 (2H, m), 7.80-7.89 (2H, m). 1174

¹H-NMR (CDCl₃) δ ppm: 0.93 (6H, d, J = 6.7 Hz), 1.41-1.75 (5H, m), 1.75-2.02 (4H, m), 2.23-2.48 (1H, m), 2.65-2.87 (6H, m), 3.06-3.25 (4H, m), 3.42-3.54 (1H, m), 3.62 (2H, t, J = 6.2 Hz), 3.85 (2H, d, J = 6.5 Hz), 6.89 (1H, d, J = 7.6 Hz), 7.20- 7.34 (1H, m), 7.34-7.46 (2H, m), 7.54 (1H, d, J = 8.0 Hz). 1175

¹H-NMR (CDCl₃) δ ppm: 1.41-1.75 (4H, m), 1.75-2.01 (4H, m), 2.18-2.44 (1H, m), 2.72-3.04 (6H, m), 3.14-3.31 (4H, m), 3.44-3.54 (1H, m), 3.64 (2H, t, J = 6.0 Hz), 6.88 (1H, d, J = 7.6 Hz), 7.20-7.31 (1H, m), 7.31-7.44 (2H, m), 7.55 (1H, d, J = 8.0 Hz).

TABLE 143

Example R1 NMR 1176

¹H-NMR (DMSO-d₆) δ ppm: 1.85-1.95 (2H, m), 2.57 (2H, t, J = 7.1 Hz), 2.60-2.75 (4H, m), 3.05-3.15 (4H, m), 4.03 (2H, t, J = 6.3 Hz), 6.85-6.95 (2H, m), 7.20-7.31 (2H, m), 7.35- 7.41 (1H, m), 7.60 (1H, d, J = 8.1 Hz), 7.68 (1H, d, J = 5.5 Hz). 1177

¹H-NMR (CDCl₃) δ ppm: 1.39 (3H, t, J = 7.0 Hz), 2.00-2.11 (2H, m), 2.60 (2H, t, J = 7.0 Hz), 2.63-2.80 (4H, m), 3.09-3.25 (4H, m), 4.24 (2H, t, J = 6.3 Hz), 4.40 (2H, q, J = 7.0 Hz), 4.64 (2H, q, J = 8.3 Hz), 6.12 (1H, s), 6.90 (1H, dd, J = 0.5 Hz, 7.5 Hz), 7.25- 7.31 (1H, m), 7.38-7.43 (2H, m), 7.56 (1H, d, J = 8.1 Hz). 1178

¹H-NMR (CDCl₃) δ ppm: 1.39 (3H, t, J = 7.0 Hz), 2.00-2.06 (2H, m), 2.60 (2H, t, J = 7.5 Hz), 2.67-2.83 (4H, m), 3.13-3.28 (4H, m), 4.18 (2H, t, J = 6.3 Hz), 4.39 (2H, q, J = 7.0 Hz), 4.61 (2H, m), 5.08-5.23 (2H, m), 5.87-6.09 (1H, m), 6.11 (1H, s), 6.75 (1H, dd, J = 0.6 Hz, 7.5 Hz), 7.25-7.37 (1H, m), 7.40-7.43 (2H, m), 7.65 (1H, d, J = 8.0 Hz). 1179

¹H-NMR (CDCl₃) δ ppm: 0.91 (3H, t, J = 7.5 Hz), 1.38 (3H, t, J = 7.0 Hz), 1.72-1.93 (2H, m), 1.98-2.13 (2H, m), 2.61 (2H, t, J = 7.3 Hz), 2.67-2.83 (4H, m), 3.09-3.28 (4H, m), 4.01 (2H, t, J = 7.0 Hz), 4.18 (2H, t, J = 6.3 Hz), 4.39 (2H, q, J = 7.0 Hz), 6.08 (1H, s), 6.90 (1H, dd, J = 0.7 Hz, 7.5 Hz), 7.25-7.30 (1H, m), 7.37-7.43 (2H, m), 7.56 (1H, d, J = 8.0 Hz).

TABLE 144

Example R1 NMR 1180

¹H-NMR (CDCl₃) δ ppm: 1.51 (9H, s), 1.97-2.12 (2H, m), 2.52-2.67 (2H, m), 2.67-2.80 (4H, m), 3.07-3.29 (4H, m), 4.38 (2H, t, J = 6.3 Hz), 6.52 (1H, br), 6.90 (1H, d, J = 7.6 Hz), 7.03 (1H, br), 7.21-7.33 (1H, m), 7.40 (2H, dd, J = 5.6 Hz, 7.3 Hz), 7.55 (1H, d, J = 8.0 Hz). 1181

¹H-NMR (CDCl₃) δ ppm: 1.95-2.13 (2H, m), 2.65-2.83 (6H, m), 3.09-3.27 (4H, m), 4.33 (2H, t, J = 6.4 Hz), 6.89 (1H, d, J = 7.6 Hz), 7.20-7.32 (1H, m), 7.40 (1H, dd, J = 5.6 Hz, 9.0 Hz), 7.54 (1H, d, J = 8.0 Hz), 7.71-7.80 (2H, m), 7.80-7.90 (2H, m). 1182

¹H-NMR (CDCl₃) δ ppm: 0.10 (6H, s), 0.92 (9H, s), 1.93-2.13 (2H, m), 2.62 (2H, t, J = 7.5 Hz), 2.70-2.83 (4H, m), 3.09-3.28 (4H, m), 3.59 (3H, s), 4.13 (2H, t, J = 6.3 Hz), 4.60 (2H, s), 5.54 (1H, s), 6.90 (1H, dd, J = 0.7 Hz, 7.5 Hz), 7.20-7.33 (1H, m), 7.35- 7.48 (2H, m), 7.55 (1H, d, J = 8.0 Hz). 1183

¹H-NMR (CDCl₃) δ ppm: 1.50 (9H, s), 1.94- 2.12 (2H, m), 2.60 (2H, t, J = 7.0 Hz), 2.66- 2.80 (4H, m), 3.10-3.27 (4H, m), 3.52 (3H, s), 4.15 (2H, t, J = 6.4 Hz), 5.85 (1H, s), 6.81-6.97 (2H, m), 7.20-7.33 (1H, m), 7.35- 7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz).

TABLE 145

Example R1 NMR 1184

¹H-NMR (CDCl₃) δ ppm: 2.01-2.20 (2H, m), 2.62-2.87 (6H, m), 3.10-3.30 (4H, m), 3.99 (3H, s), 4.20 (2H, t, J = 6.3 Hz), 6.91 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.20 (1H, d, J = 2.6 Hz), 7.22-7.34 (2H, m), 7.35-7.50 (3H, m), 7.55 (1H, d, J = 8.1 Hz), 7.90 (1H, d, J = 8.1 Hz), 8.03 (1H, dd, J = 1.2 Hz, 7.3 Hz), 8.83 (1H, d, J = 9.4 Hz). 1185

¹H-NMR (CDCl₃) δ ppm: 1.46 (9H, s), 1.45- 1.60 (2H, m), 1.75-1.90 (4H, m), 2.50-2.60 (2H, m), 2.65-2.80 (4H, m), 3.05-3.25 (6H, m), 3.40-3.50 (1H, m), 3.53 (2H, t, J = 6.4 Hz), 3.70-3.80 (2H, m), 6.89 (1H, dd, J = 7.6, 0.7 Hz), 7.20-7.30 (1H, m), 7.35- 7.45 (2H, m), 7.54 (1H, d, J = 8.0 Hz), 8.02 (1H, s). 1186

¹H-NMR (CDCl₃) δ ppm: 1.30-1.60 (2H, m), 1.75-2.00 (4H, m), 2.50-2.75 (4H, m), 3.05- 3.25 (6H, m), 3.30-3.40 (1H, m), 3.55 (2H, t, J = 6.5 Hz), 6.90 (1H, d, J = 7.6 Hz), 7.20- 7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.1 Hz). 1187

¹H-NMR (CDCl₃) δ ppm: 1.38 (3H, t, J = 7.1 Hz), 2.00-2.10 (2H, m), 2.60 (2H, t, J = 7.1 Hz), 2.65-2.75 (4H, m), 3.15-3.25 (4H, m), 3.72 (3H, s), 4.17 (2H, t, J = 6.4 Hz), 4.38 (2H, q, J = 7.1 Hz), 6.08 (1H, s), 6.89 (1H, d, J = 7.6 Hz), 7.20-7.30 (1H, m), 7.35-7.45 (2H, m), 7.54 (1H, d, J = 8.1 Hz). 1188

¹H-NMR (CDCl₃) δ ppm: 1.94-2.10 (2H, m), 2.60 (2H, t, J = 7.1 Hz), 2.65-2.78 (4H, m), 3.10-3.25 (4H, m), 3.57 (3H, s), 4.15 (2H, t, J = 6.3 Hz), 5.93 (1H, s), 6.89 (1H, d, J = 7.5 Hz), 7.12-7.32 (3H, m), 7.33-7.45 (4H, m), 7.55 (1H, d, J = 8.0 Hz), 7.93 (1H, br).

TABLE 146

Example R1 NMR 1189

¹H-NMR (CDCl₃) δ ppm: 1.75-2.00 (4H, m), 2.50-2.60 (2H, m), 2.70-2.75 (4H, m), 3.15-3.25 (4H, m), 3.35-3.80 (6H, m), 4.00-4.05 (1H, m), 6.91 (1H, dd, J = 7.6, 0.5 Hz), 7.25-7.35 (1H, m), 7.35-7.45 (2H, m), 7.56 (1H, d, J = 8.0 Hz). 1190

¹H-NMR (CDCl₃) δ ppm: 1.75-1.95 (4H, m), 2.51 (2H, t, J = 7.1 Hz), 2.50-2.75 (8H, m), 3.10-3.20 (4H, m), 3.46 (2H, t, J = 6.3 Hz), 4.00-4.10 (1H, m), 6.88 (1H, d, J = 7.1 Hz), 7.20-7.30 (1H, m), 7.30- 7.45 (2H, m), 7.53 (1H, d, J = 8.0 Hz).

TABLE 147

Example R1 NMR 1191

¹H-NMR (CDCl₃) δ ppm:: 1.50 (9H, s), 1.59-1.77 (2H, m), 1.77-1.93 (2H, m), 2.50 (2H, t, J = 7.3 Hz), 2.61-2.80 (4H, m), 3.11-3.27 (4H, m), 3.54 (3H, s), 4.09 (2H, t, J = 6.3 Hz), 5.85 (1H, s), 6.90 (1H, d, J = 7.5 Hz), 7.23-7.32 (1H, m), 7.36-7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 7.80 (1H, br). 1192

¹H-NMR (CDCl₃) δ ppm:: 1.64-1.93 (4H, m), 2.51 (2H, t, J = 7.3 Hz), 2.61-2.79 (4H, m), 3.11-3.29 (4H, m), 3.46 (3H, s), 3.49 (2H, br), 4.02 (2H, t, J = 6.2 Hz), 4.94 (1H, s), 6.90 (1H, dd, J = 0.7 hz, 7.6 Hz), 7.22-7.33 (1H, m), 7.35-7.46 (2H, m), 7.55 (1H, d, J = 8.0 Hz). 1193

¹H-NMR (CDCl₃) δ ppm:: 1.64-1.78 (2H, m), 1.78-1.94 (2H, m), 2.50 (2H, t, J = 7.3 Hz), 2.61-2.81 (4H, m), 3.10-3.28 (4H, m), 3.57 (3H, s), 4.09 (2H, t, J = 6.3 Hz), 5.92 (1H, s), 6.77-6.98 (4H, m), 7.11- 7.32 (2H, m), 7.32-7.47 (4H, m), 7.55 (1H, d, J = 8.0 Hz), 8.47 (1H, br).

TABLE 148

Example R1 MS(M + 1) 1194 —CO₂CH₂C₆H₅ 603 1195 —CO₂C₂H₅ 541 1196 —COCH₃ 511 1197 —CO₂C(CH₃)₃ 569 1198 —COC₆H₅ 573 1199 —COC₃H₇ 539 1200

563

TABLE 149

Example R1 MS(M + 1) 1201 —CO₂CH₂C₆H₅ 617 1202 —CO₂C₂H₅ 555 1203 —COCH₃ 525 1204 —CO₂C(CH₃)₃ 583 1205 —COC₆H₅ 587 1206 —COC₃H₇ 553 1207

577

TABLE 150

Example R1 R2 R3 R4 R5 MS(M + 1) 1208 —H —H —H —Cl —H 608 1209 —H —H —H —H —F 592 1210 —H —H —H —H —Cl 608 1211 —H —H —Cl —Cl —H 642 1212 —H —H —H —OCH₃ —H 604 1213 —H —OCH₃ —H —OCH₃ —H 634 1214 —H —H —CH₃ —H —H 588 1215 —H —H —H —CH₃ —H 588 1216 —H —H —H —H —CH₃ 588 1217 —H —H —F —H —H 592 1218 —H —H —H —F —H 592 1219 —H —H —OCF₃ —H —H 658 1220 —H —H —H —OCF₃ —H 658 1221 —H —H —H —H —OCF₃ 658 1222 —H —H —OCH₃ —Cl —H 638 1223 —H —H —H —Br —H 652 1224 —H —H —OCH₃ —H —H 604 1225 —H —H —H —H —H 574

TABLE 151

Example R1 R2 R3 R4 R5 MS(M + 1) 1226 —H —H —H —Cl —H 622 1227 —H —H —H —H —F 606 1228 —H —H —H —H —Cl 622 1229 —H —H —Cl —Cl —H 656 1230 —H —H —H —OCH₃ —H 618 1231 —H —OCH₃ —H —OCH₃ —H 648 1232 —H —H —CH₃ —H —H 602 1233 —H —H —H —CH₃ —H 602 1234 —H —H —H —H —CH₃ 602 1235 —H —H —F —H —H 606 1236 —H —H —H —F —H 606 1237 —H —H —OCF₃ —H —H 672 1238 —H —H —H —OCF₃ —H 672 1239 —H —H —H —H —OCF₃ 672 1240 —H —H —OCH₃ —Cl —H 652 1241 —H —H —H —Br —H 666 1242 —H —H —OCH₃ —H —H 618 1243 —H —H —H —H —H 588

TABLE 152

Example R1 R2 R3 R4 R5 MS(M + 1) 1244 —H —H —CN —H —H 585 1245 —H —H —H —H —OCH₃ 590 1246 —H —H —H —OCH₃ —H 590 1247 —H —H —OCH₃ —H —H 590 1248 —H —H —H —H —H 560 1249 —H —H —H —H —Cl 594 1250 —H —H —H —Cl —H 594 1251 —H —H —Cl —H —H 594 1252 —H —H —H —H —CH₃ 574 1253 —H —H —CH₃ —H —H 574 1254 —H —H —F —H —H 578 1255 —H —H —CF3 —H —H 628

TABLE 153

Example R1 R2 R3 R4 R5 MS(M + 1) 1256 —H —H —CN —H —H 599 1257 —H —H —H —H —OCH₃ 604 1258 —H —H —H —OCH₃ —H 604 1259 —H —H —OCH₃ —H —H 604 1260 —H —H —H —H —H 574 1261 —H —H —H —H —Cl 608 1262 —H —H —H —Cl —H 608 1263 —H —H —Cl —H —H 608 1264 —H —H —H —H —CH₃ 588 1265 —H —H —CH₃ —H —H 588 1266 —H —H —F —H —H 592 1267 —H —H —CF₃ —H —H 642

TABLE 154

Example R1 MS(M + 1) 1268 —OCH₃ 498 1269 —CH₂CONHC₂H₅ 553 1270 —OH 484 1271 —CO₂C₂H₅ 540 1272 —CONH₂ 511 1273 —CH₂OH 498 1274 —N(CH₃)CO₂C(CH₃)₃ 597 1275 —NHCO₂C(CH₃)₃ 583 1276 —CO₂C(CH₃)₃ 568 1277 —NHCOCH₃ 525 1278 —N(CH₃)COCH₃ 539 1279 —COOH 512 1280 —N(CH₃)CO(CH₂)₂CH₃ 567 1281 —NHCO(CH₂)₂CH₃ 553

TABLE 155

Example R1 MS(M + 1) 1282

578 1283

574 1284

560 1285

592 1286

572 1287

558 1288

602 1289

588 1290

642 1291

606 1292

602

TABLE 156

Example R1 MS(M + 1) 1293

590 1294

572 1295

545 1296

561 1297

561 1298

575 1299

575 1300

587 1301

601

TABLE 157

Example R1 MS(M + 1) 1302

651 1303

655 1304

593 1305

621

TABLE 158

Example R1 MS(M + 1) 1306

592 1307

588 1308

574 1309

606 1310

586 1311

572 1312

616 1313

602 1314

656 1315

620 1316

616

TABLE 159

Example R1 MS(M + 1) 1317 —OCH₃ 512 1318 —CH₂CONHC₂H₅ 567 1319 —OH 498 1320 —CO₂C₂H₅ 554 1321 —CONH₂ 525 1322 —CH₂OH 512 1323 —N(CH₃)CO₂C(CH₃)₃ 611 1324 —NHCO₂C(CH₃)₃ 597 1325 —CO₂C(CH₃)₃ 582 1326 —NHCOCH₃ 539 1327 —N(CH₃)COCH₃ 553 1328 —N(CH₃)CO(CH₂)₂CH₃ 581 1329 —NHCO(CH₂)₂CH₃ 567 1330 —COOH 526

TABLE 160

Example R1 MS(M + 1) 1331

604 1332

586 1333

559 1334

575 1335

575 1336

589 1337

589 1338

601 1339

615

TABLE 161

Example R1 MS(M + 1) 1340

665 1341

669 1342

607 1343

635

TABLE 162

Example R1 MS(M + 1) 1344

644 1345

630 1346

497 1347

599 1348

511 1349

587 1350

573 1351

525 1352

553 1353

539

TABLE 163

Example R1 MS(M + 1) 1354

480 1355

472 1356

578 1357

573 1358

496 1359

544 1360

560 1361

594

TABLE 164

Example R1 MS(M + 1) 1362

540 1363

600 1364

627 1365

484 1366

540 1367

512 1368

574 1369

526 1370

614

TABLE 165

Example R1 MS(M + 1) 1371

543 1372

486 1373

470 1374

498 1375

546 1376

559 1377

539 1378

483 1379

593 1380

573

TABLE 166

Example R1 MS(M + 1) 1381

468 1382

658 1383

644 1384

511 1385

613 1386

484 1387

525 1388

601 1389

587 1390

539 1391

567 1392

553

TABLE 167

Example R1 MS(M + 1) 1393

494 1394

486 1395

592 1396

587 1397

499 1398

510 1399

558 1400

574 1401

608

TABLE 168

Example R1 MS(M + 1) 1402

554 1403

614 1404

641 1405

498 1406

554 1407

526 1408

588 1409

540 1410

628

TABLE 169

Example R1 MS(M + 1) 1411

557 1412

500 1413

484 1414

512 1415

560 1416

573 1417

553 1418

497 1419

607 1420

587

TABLE 170

Example R1 R2 R3 R4 R5 MS(M + 1) 1421 —H —H —OCF₃ —H —H 560 1422 —H —H —H —H —SO₂NH₂ 555 1423 —H —H —OCH₃ —H —H 506 1424 —H —H —H —OCH₃ —H 506 1425 —H —H —COCH₃ —H —H 518 1426 —H —H —H —H —CO₂CH₃ 534 1427 —H —H —OCH₃ —H —OCH₃ 536 1428 —OCH₃ —H —H —OCH₃ —H 536 1429 —H —OCH₃ —H —OCH₃ —H 536 1430 —OCH₃ —H —H —NHCOCH₃ —H 563 1431 —H —H —OCH₃ —OCH₃ —H 536 1432 —H —H —N(CH₃)₂ —H —H 519 1433 —H —H —H —COCH₃ —H 518 1434 —H —H —H —NHCOCH₃ —H 533 1435 —H —H —NHCOCH₃ —H —H 533 1436 —H —CN —H —H —H 501 1437 —OCH₃ —H —H —CO₂CH₃ —H 564 1438 —H —H —OC₆H₅ —H —H 568 1439 —H —CO₂CH₃ —H —CO₂CH₃ —H 592 1440 —H —H —OH —Cl —H 526 1441 —Cl —H —H —NHCOCH₃ —H 567 1442 —H —CN —H —H —Cl 535 1443 —Cl —H —H —CONH₂ —H 553 1444 —H —H —NO₂ —H —H 521 1445 —H —H —CN —H —H 501

TABLE 171

Example R1 R2 R3 R4 R5 MS(M + 1) 1446 —H —H

—H —H 558 1447 —H —H

—H —H 584 1448 —H —H

—H —H 561 1449 —H —H

—H —H 605 1450 —H —H —H

—H 587 1451 —H —H —H

—H 542

TABLE 172

Example R1 R2 R3 R4 R5 MS(M + 1) 1452 —H —H —OCF₃ —H —H 574 1453 —H —H —OCH₃ —H —H 520 1454 —H —OCH₃ —H —H —H 520 1455 —H —H —COCH₃ —H —H 532 1456 —CO₂CH₃ —H —H —H —H 548 1457 —OCH₃ —H —OCH₃ —H —H 550 1458 —H —OCH₃ —H —H —OCH₃ 550 1459 —H —OCH₃ —H —OCH₃ —H 550 1460 —H —NHCOCH₃ —H —H —OCH₃ 577 1461 —H —OCH₃ —OCH₃ —H —H 550 1462 —H —H —N(CH₃)₂ —H —H 533 1463 —H —COCH₃ —H —H —H 532 1464 —H —NHCOCH₃ —H —H —H 547 1465 —H —H —NHCOCH₃ —H —H 547 1466 —H —CO₂CH₃ —H —H —OCH₃ 578 1467 —H —H —OC₆H₅ —H —H 582 1468 —H —CO₂CH₃ —H —CO₂CH₃ —H 606 1469 —OCH₃ —OCH₃ —H —H —H 550 1470 —H —Cl —OH —H —H 540 1471 —H —OCH₂C₆H₅ —H —H —H 596 1472 —H —H —NHSO₂CH₃ —H —H 583 1473 —H —H —CONHC₆H₅ —H —H 609 1474 —H —H —CONHCH₃ —H —H 547 1475 —H —H —NHC₆H₅ —H —H 581 1476 —H —H —CH₂CH₂OH —H —H 534 1477 —H —H —CCH —H —H 514 1478 —H —H —COC₃H₇ —H —H 560 1479 —NHCOCH₃ —H —H —H —H 547 1480 —H —CONHCH₃ —H —H —H 547

TABLE 173

Example R1 R2 R3 R4 R5 MS(M + 1) 1481 —H —H

—H —H 573 1482 —H —H

—H —H 572 1483 —H

—H —H —H 601 1484 —H

—H —H —H 556 1485 —H

—H —H —H 557

TABLE 174

Example R1 R2 R3 R4 R5 R6 MS(M + 1) 1486 —H —H —H —H —H —H 490 1487 —Cl —H —H —H —H —H 524 1488 —H —Cl —H —H —H —H 524 1489 —H —H —Cl —H —H —H 524 1490 —H —H —H —H —H —CH₂CONHCH₃ 561 1491 —H —H —OC₂H₅ —H —H —CH₃ 548 1492 —H —OCH₃ —OCH₃ —H —H —CH₃ 564 1493 —H —H —OC₂H₅ —H —H —C₂H₅ 562 1494 —H —H —OCH₃ —H —H —H 520 1495 —H —OCH₃ —H —H —H —H 520 1496 —H —H —OCF₃ —H —H —CH₃ 588 1497 —H —H —OCF₃ —H —H —H 574 1498 —H —OCH₃ —OCH₃ —H —H —H 550 1499 —H —OCH₃ —OCH₃ —H —H —C₂H₅ 578 1500 —OCH₃ —H —H —H —H —H 520 1501 —H —OCH₃ —H —OCH₃ —H —H 550 1502 —H —OC₄H₉ —H —OC₄H₉ —H —H 634 1503 —OC₂H₅ —H —H —H —H —H 534 1504 —H —H —H —H —H —(CH₂)₃OH 548 1505 —H —Cl —OCHF₂ —H —H —H 590 1506 —H —OCF₃ —H —H —H —H 574 1507 —H —H —OCH₃ —H —H —CH₃ 534

TABLE 175

Example R1 R2 R3 R4 R5 R6 MS(M + 1) 1508 —H —H —H —H —H —H 504 1509 —Cl —H —H —H —H —H 538 1510 —H —Cl —H —H —H —H 538 1511 —H —H —Cl —H —H —H 538 1512 —H —H —H —H —H —CH₂CONHCH₃ 575 1513 —H —H —OC₂H₅ —H —H —CH₃ 562 1514 —H —OCH₃ —OCH₃ —H —H —CH₃ 578 1515 —H —H —OC₂H₅ —H —H —C₂H₅ 576 1516 —H —H —OCH₃ —H —H —H 534 1517 —H —OCH₃ —H —H —H —H 534 1518 —H —H —OCF₃ —H —H —CH₃ 602 1519 —H —H —OCF₃ —H —H —H 588 1520 —H —OCH₃ —OCH₃ —H —H —H 564 1521 —H —OCH₃ —OCH₃ —H —H —C₂H₅ 592 1522 —OCH₃ —H —H —H —H —H 534 1523 —H —OCH₃ —H —OCH₃ —H —H 564 1524 —H —OC₄H₉ —H —OC₄H₉ —H —H 648 1525 —OC₂H₅ —H —H —H —H —H 548 1526 —H —H —H —H —H —(CH₂)₃OH 562 1527 —H —Cl —OCHF₂ —H —H —H 604 1528 —H —OCF₃ —H —H —H —H 588 1529 —H —H —OCH₃ —H —H —CH₃ 548

TABLE 176

MS Example R1 R2 (M + 1) 1530 -cyclo-C₆H₁₁ —CH₃ 496 1531 -cyclo-C₆H₁₁ —H 482 1532 —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ 512 1533 —CH₂CH₂OH —CH₂CH₂OH 488 1534 —CH₂CH₂OH —C₂H₅ 472 1535 -cyclo-C₆H₁₁ —CH₂CH₂OH 526 1536 —CH₂CH₂OCH₃ —CH₂CH₂OCH₃ 516 1537 —C₂H₅ —C₂H₅ 456 1538 —C₄H₉ —H 456 1539 —C(CH₃)₃ —H 456 1540 -cyclo-C₃H₅ —H 440 1541 —CH₃ —H 414 1542 —C₂H₅ —H 428 1543 —CH₂CH(CH₃)₂ —H 456 1544 —CH₂CH₂OCH₃ —H 458 1545 —CH₂CH₂OC₂H₅ —H 472 1546 —(CH₂)₃OC₂H₅ —H 486 1547 —(CH₂)₂OC₆H₅ —H 520 1548 —CH₂-cyclo-C₃H₅ —H 454 1549 —(CH₂)₂NHCOCH₃ —H 485 1550 —(CH₂)₅OH —H 486 1551 —(CH₂)₂C₆H₅ —H 504 1552 —CH₂CO₂CH₃ —H 472 1553 —CH₂CONH₂ —H 457 1554 —CH(CO₂C₂H₅)₂ —H 558 1555 —CH(CH₃)CO₂C₂H₅ —H 500 1556 —CH₂CO₂CH₃ —CH₃ 486 1557 —CH₂CCH —H 438 1558 —(CH₂)₂CH(CH₃)₂ —H 470 1559 —(CH₂)₃CO₂C₂H₅ —CH₃ 528 1560 —(CH₂)₄CO₂C₂H₅ —H 528 1561 —CH(CONH₂)₂ —H 500 1562 —CH₂CF₃ —H 482 1563 —NHCH₂CF₃ —H 497 1564 —CH₃ —CH₃ 428 1565 —(CH₂)₃OCH(CH₃)₂ —H 500

TABLE 177

Example R1 R2 MS(M + 1) 1566 —CH₂CN —H 439 1567 —(CH₂)₂OCH(CH₃)₂ —H 486 1568 —CH(C₂H₅)CH₂OCH₃ —H 486 1569 —CH(CH₃)CH₂OCH₃ —H 472 1570 —CH₂CH₂F —H 446 1571 —CH₂CH(OH)CH₂OH —H 474 1572 —CH₂CONHCH₃ —H 471 1573 —(CH₂)₂SCH₃ —H 474 1574 —CH₂CH₂OH —H 444 1575 —C₆H₁₃ —H 484 1576 —CH₂CON(CH₃)₂ —CH₃ 499 1577 —(CH₂)₂N(CH₃)COCH₃ —H 499 1578 —(CH₂)₂N(CH₃)CO(CH₂)₂CH₃ —H 527

TABLE 178

Exam- MS ple R1 R2 (M + 1) 1579

—CH₃ 519 1580

—C₂H₅ 526 1581

—H 518 1582

—H 491 1583

—H 491 1584

—H 491 1585

—H 480 1586

—C₂H₅ 533 1587

—C₂H₅ 578 1588

—CH₃ 534 1589

—C₂H₅ 591 1590

—C₂H₅ 633

TABLE 179

Example R1 R2 MS(M + 1) 1591

—C₂H₅ 631 1592

—CH₃ 601 1593

—CH₃ 539 1594

—CH₃ 548 1595

—C₂H₅ 562 1596

—C₂H₅ 592 1597

—H 454 1598

—H 534 1599

—H 534 1600

—H 538 1601

—H 534 1602

—H 498 1603

—H 508

TABLE 180

Example R1 R2 MS(M + 1) 1604

—H 562 1605

—H 548 1606

—H 578 1607

—H 514 1608

—H 528 1609

—H 537 1610

—H 499 1611

—H 547 1612

—H 601 1613

—H 552 1614

—H 484

TABLE 181

Exam- MS ple R1 R2 (M + 1) 1615

—H 471 1616

—H 485 1617

—CH₃ 577 1618

—CH₃ 561 1619

—H 534 1620

—H 518 1621

—H 518 1622

—H 545 1623

—H 559 1624

—H 505 1625

—CH(CH₃)₂ 547 1626

—CH₃ 619

TABLE 182

Exam- MS ple R1 R2 (M + 1) 1627

—CH₃ 615 1628

—CH₃ 615 1629

—CH₃ 615 1630

—CH₃ 635 1631

—CH₃ 635 1632

—C₄H₉ 657 1633

—CH(CH₃)₂ 643 1634

—H 583 1635

—H 569 1636

—C₂H₅ 573 1637

—H 540

TABLE 183

Exam- MS ple R1 R2 (M + 1) MW 1638

—H 558 557.72 1639

—H 558 557.68 1640

—H 572 571.70 1641

—H 543 542.71 1642

—H 530 529.67 1643

—H 559 558.63 1644

—H 525 524.69 1645

—H 484 483.64 1646

—H 506 505.65 1647

—H 486 485.61 1648

—H 505 504.66 1649

—H 505 504.66

TABLE 184

Example R1 R2 MS(M + 1) 1650

—H 494 1651

—H 494 1652

—H 493 1653

—H 522 1654

—H 508 1655

—H 508 1656

—H 480 1657

—H 497 1658

—H 510 1659

—H 532 1660

—H 454 1661

—H 524

TABLE 185

Example R1 R2 MS(M + 1) 1662

—H 498 1663

—H 588 1664

—CH₃ 580 1665

—H 516 1666

—H 494 1667

—H 505 1668

—H 562 1669

—H 543 1670

—H 574 1671

—H 574

TABLE 186

Exam- MS ple R1 R2 (M + 1) 1672

—H 484 1673

—H 587 1674

—H 573 1675

—H 561 1676

—H 615 1677

—H 559 1678

—H 573 1679

—H 587 1680

—H 525 1681

—H 511

TABLE 187

Exam- MS ple R1 R2 (M + 1) 1682

—H 553 1683

—H 497 1684

—H 511 1685

—H 525 1686

—H 553 1687

—H 539 1688

—H 581 1689

—H 525 1690

—H 539 1691

—H 553 1692

—H 477

TABLE 188

Example R1 R2 MS(M + 1) 1693

—H 516 1694

—H 477 1695

—H 507 1696

—H 575 1697

—H 515 1698

—H 483 1699

—H 540 1700

—H 467 1701

—H 443 1702

—H 481 1703

—H 557

TABLE 189

Example R1 R2 MS(M + 1) 1704

—H 531 1705

—H 540 1706

—H 527 1707

—H 498 1708

—H 509 1709

—H 532 1710

—H 481 1711

—H 480 1712

—H 497 1713

—H 467

TABLE 190

Example R1 R2 MS(M + 1) 1714 —CH₃ -cyclo-C₆H₁₁ 510 1715 —H -cyclo-C₆H₁₁ 496 1716 —H —CH(CH₃)₂ 456 1717 —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ 526 1718 —CH₂CH₂OH —CH₂CH₂OH 502 1719 —C₂H₅ —CH₂CH₂OH 486 1720 —CH₂CH₂OH -cyclo-C₆H₁₁ 540 1721 —CH₂CH₂OCH₃ —CH₂CH₂OCH₃ 530 1722 —C₂H₅ —C₂H₅ 470 1723 —H —C₄H₉ 470 1724 —H —C(CH₃)₃ 470 1725 —H -cyclo-C₃H₅ 454 1726 —H —CH₃ 428 1727 —H —C₂H₅ 442 1728 —H —C₃H₇ 456 1729 —H —CH₂CH(CH₃)₂ 470 1730 —H —CH₂CH₂OCH₃ 472 1731 —H —CH₂CH₂OC₂H₅ 486 1732 —H —(CH₂)₃OC₂H₅ 500 1733 —H —(CH₂)₂OC₆H₅ 534 1734 —H —CH₂-cyclo-C₃H₅ 468 1735 —H —(CH₂)₂NHCOCH₃ 499 1736 —H —(CH₂)₅OH 500 1737 —H —(CH₂)₂C₆H₅ 518 1738 —H —CH₂CO₂CH₃ 486 1739 —H —CH₂CONH₂ 471 1740 —H —CH(CO₂C₂H₅)₂ 572 1741 —H —CH(CH₃)CO₂C₂H₅ 514 1742 —CH₃ —CH₂CO₂CH₃ 500 1743 —H —CH₂CCH 452 1744 —H —(CH₂)₂CH(CH₃)₂ 484 1745 —CH₃ —(CH₂)₃CO₂C₂H₅ 542 1746 —H —(CH₂)₄CO₂C₂H₅ 542 1747 —H —CH(CONH₂)₂ 514 1748 —H —CH₂CF₃ 496 1749 —H —NHCH₂CF₃ 511

TABLE 191

Example R1 R2 MS(M + 1) 1750 —CH₃ —CH₃ 442 1751 —H —CH₂CH(OCH₃)₂ 502 1752 —H —(CH₂)₃OCH(CH₃)₂ 514 1753 —H —CH₂CN 453 1754 —H —(CH₂)₃OCH₃ 486 1755 —H —(CH₂)₂OCH(CH₃)₂ 500 1756 —H —CH(C₂H₅)CH₂OCH₃ 500 1757 —H —CH(CH₃)CH₂OCH₃ 486 1758 —H —CH₂CH₂F 460 1759 —H —CH₂CH(OH)CH₂OH 488 1760 —H —CH₂CONHCH₃ 485 1761 —H —(CH₂)₂SCH₃ 488 1762 —H —CH₂CH₂OH 458 1763 —H —C₆H₁₃ 498 1764 —CH₃ —CH₂CON(CH₃)₂ 513 1765 —H —(CH₂)₂N(CH₃)COCH₃ 513 1766 —H —(CH₂)₂N(CH₃)CO(CH₂)₂CH₃ 541

TABLE 192

MS Example R1 R2 (M + 1) 1767

—CH₃ 533 1768

—C₂H₅ 540 1769

—H 532 1770

—H 505 1771

—H 505 1772

—H 505 1773

—H 494 1774

—C₂H₅ 547 1775

—C₂H₅ 592 1776

—CH₃ 548 1777

—C₂H₅ 605 1778

—C₂H₅ 647

TABLE 193

MS Example R1 R2 (M + 1) 1779

—C₂H₅ 645 1780

—CH₃ 615 1781

—CH₃ 553 1782

—CH₃ 562 1783

—C₂H₅ 576 1784

—C₂H₅ 606 1785

—H 468 1786

—H 548 1787

—H 548 1788

—H 552 1789

—H 548 1790

—H 512 1791

—H 522

TABLE 194

MS Example R1 R2 (M + 1) 1792

—H 576 1793

—H 562 1794

—H 592 1795

—H 528 1796

—H 542 1797

—H 551 1798

—H 513 1799

—H 561 1800

—H 615 1801

—H 566 1802

—H 498

TABLE 195

MS Example R1 R2 (M + 1) 1803

—H 485 1804

—H 499 1805

—CH₃ 591 1806

—CH₃ 575 1807

—H 548 1808

—H 532 1809

—H 532 1810

—H 559 1811

—H 573 1812

—H 519 1813

—CH(CH₃)₂ 561 1814

—H 470

TABLE 196

MS Example R1 R2 (M + 1) 1815

—CH₃ 633 1816

—CH₃ 629 1817

—CH₃ 629 1818

—CH₃ 629 1819

—CH₃ 649 1820

—C₄H₉ 649 1821

—C₄H₉ 671 1822

—CH(CH₃)₂ 657 1823

—H 597 1824

—H 583 1825

—C₂H₅ 587

TABLE 197

Example R1 R2 MS(M + 1) 1826

—H 554 1827

—H 572 1828

—H 572 1829

—H 586 1830

—H 557 1831

—H 544 1832

—H 573 1833

—H 539 1834

—H 498 1835

—H 520 1836

—H 500

TABLE 198

Example R1 R2 MS(M + 1) 1837

—H 519 1838

—H 519 1839

—H 508 1840

—H 508 1841

—H 507 1842

—H 536 1843

—H 522 1844

—H 522 1845

—H 494 1846

—H 511 1847

—H 524 1848

—H 546 1849

—H 538

TABLE 199

Example R1 R2 MS(M + 1) 1850

—H 512 1851

—H 602 1852

—CH₃ 594 1853

—H 530 1854

—H 508 1855

—H 519 1856

—H 576 1857

—H 557 1858

—H 588 1859

—H 588 1860

—H 498

TABLE 200

Example R1 R2 MS(M + 1) 1861

—H 601 1862

—H 587 1863

—H 575 1864

—H 629 1865

—H 573 1866

—H 587 1867

—H 601 1868

—H 539 1869

—H 525 1870

—H 567

TABLE 201

MS Example R1 R2 (M + 1) 1871

—H 511 1872

—H 525 1873

—H 539 1874

—H 567 1875

—H 553 1876

—H 595 1877

—H 539 1878

—H 553 1879

—H 567 1880

—H 491 1881

—H 530

TABLE 202

MS Example R1 R2 (M + 1) 1882

—H 541 1883

—H 505 1884

—CH₃ 520 1885

—CH₃ 612 1886

—H 521 1887

—H 589 1888

—H 529 1889

—H 577 1890

—H 505 1891

—H 497 1892

—H 541

TABLE 203

Example R1 R2 MS(M + 1) 1893

—H 456 1894

—H 545 1895

—H 508 1896

—H 546 1897

—H 494 1898

—H 555

TABLE 204

Example R1 R2 R3 R4 R5 MS(M + 1) 1899 —H —H —OCF₃ —H —H 562 1900 —H —H —OCH₃ —H —H 508 1901 —H —OCH₃ —H —H —H 508 1902 —OCH₃ —H —OCH₃ —H —H 538 1903 —H —OCH₃ —H —H —OCH₃ 538 1904 —H —OCH₃ —H —OCH₃ —H 538 1905 —H —NHCOCH₃ —H —H —OCH₃ 565 1906 —H —OCH₃ —OCH₃ —H —H 538 1907 —H —H —N(CH₃)₂ —H —H 521 1908 —H —COCH₃ —H —H —H 520 1909 —H —NHCOCH₃ —H —H —H 535 1910 —H —H —NHCOCH₃ —H —H 535 1911 —H —H —H —CN —H 503 1912 —H —CO₂CH₃ —H —H —OCH₃ 566 1913 —H —H —OC₆H₅ —H —H 570 1914 —H —CO₂CH₃ —H —CO₂CH₃ —H 594 1915 —OCH₃ —OCH₃ —H —H —H 538 1916 —H —Cl —OH —H —H 528 1917 —CO₂C₂H₅ —H —H —H —Cl 584 1918 —H —H —CN —H —H 503 1919 —H —OCH₂C₆H₅ —H —H —H 584 1920 —H —H —NHSO₂CH₃ —H —H 571 1921 —H —H —CONHC₆H₅ —H —H 597 1922 —H —H —CONHCH₃ —H —H 535 1923 —H —H —NHC₆H₅ —H —H 569 1924 —H —H —CH₂CH₂OH —H —H 522 1925 —H —H —C≡CH —H —H 502 1926 —NHCOCH₃ —H —H —H —H 535 1927 —H —CONHCH₃ —H —H —H 535

TABLE 205

Ex- MS am- (M + ple R1 R2 R3 R4 R5 1) 1928 —H —H

—H —H 561 1929 —H —H

—H —H 607 1930 —H

—H —H —H 589 1931 —H

—H —H —H 545

TABLE 206

MS Example R1 R2 (M + 1) 1932 —CH₃ -cyclo-C₆H₁₁ 498 1933 -cyclo-C₆H₁₁ —H 484 1934 —C₄H₉ —C₄H₉ 514 1935 —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ 514 1936 —CH₂CH₂OH —CH₂CH₂OH 490 1937 —C₂H₅ —CH₂CH₂OH 474 1938 —CH₂CH₂OH -cyclo-C₆H₁₁ 528 1939 —CH₂CH₂OCH₃ —CH₂CH₂OCH₃ 518 1940 —C₃H₇ —CH₂-cyclo-C₃H₅ 498 1941 -cyclo-C₅H₉ —CH₂CH═CH₂ 510 1942 —C₂H₅ —C₂H₅ 458 1943 —C₄H₉ —H 458 1944 —C(CH₃)₃ —H 458 1945 -cyclo-C₃H₅ —H 442 1946 —C₂H₅ —H 430 1947 —CH₂CH₂OCH₃ —H 460 1948 —C₄H₉ —C₂H₅ 486 1949 —CH₂CH₂OC₂H₅ —H 474 1950 —(CH₂)₃OC₂H₅ —H 488 1951 -cyclo-C₅H₉ —H 470 1952 —CH₂-cyclo-C₃H₅ —H 456 1953 —CH₂-cyclo-C₆H₁₁ —H 498 1954 —(CH₂)₂NHCOCH₃ —H 487 1955 —(CH₂)₅OH —H 488 1956 —CH₂CONH₂ —H 459 1957 —CH₂C≡CH —H 440 1958 —CH₃ —CH(CH₃)₂ 458 1959 —(CH₂)₂CH(CH₃)₂ —H 472 1960 —CH(CH₃)C(CH₃)₃ —H 486 1961 —CH₂C(CH₃)₃ —H 472 1962 —CH₂CH(C₂H₅)₂ —H 486 1963 —CH(CONH₂)₂ —H 502 1964 —CH₂-cyclo-C₃H₅ —CH₃ 470 1965 —CH(CONH₂)₂ —H 499

TABLE 207

Example R1 R2 MS(M + 1) 1966 —CH₃ —CH₃ 430 1967 —(CH₂)₃OCH(CH₃)₂ —H 502 1968 —CH₂CH₂C(CH₃)₃ —H 486 1969 —CH(C₂H₅)₂ —H 472 1970 —CH₂CN —H 441 1971 —(CH₂)₃OCH₃ —H 474 1972 —(CH₂)₂OCH(CH₃)₂ —H 488 1973 —CH(C₂H₅)CH₂OCH₃ —H 488 1974 —CH(CH₃)CH₂OCH₃ —H 474 1975 —CH₂CH₂F —H 448 1976 —CH₂CH(OH)CH₂OH —H 476 1977 —CH₂CONHCH₃ —H 473 1978 —(CH₂)₂SCH₃ —H 476 1979 —CH₂CH₂OH —H 446 1980 —CH₂CHF₂ —H 466 1981 —C₆H₁₃ —H 486 1982 —CH₂CH₂NHCONH₂ —H 488

TABLE 208

Example R1 R2 MS(M + 1) 1983

—CH₃ 508 1984

—H 479 1985

—H 479 1986

—H 479 1987

—H 493 1988

—H 509 1989

—H 493 1990

—H 485 1991

—H 486 1992

—H 500 1993

—H 470 1994

—H 496 1995

—H 529

TABLE 209

Example R1 R2 MS(M + 1) 1996

—H 511 1997

—H 469 1998

—H 518 1999

—H 517 2000

—H 533 2001

—H 518 2002

—H 551 2003

—H 529 2004

—H 529 2005

—H 543 2006

—H 577

TABLE 210

Example R1 R2 MS(M + 1) 2007

—H 565 2008

—H 561 2009

—H 444 2010

—C₂H₅ 528 2011

—H 482 2012

—H 456 2013

—H 484 2014

—H 500 2015

—H 510 2016

—H 473 2017

—H 487 2018

—H 472 2019

—H 498

TABLE 211

Example R1 R2 MS(M + 1) 2020

—H 498 2021

—C₂H₅ 484 2022

—H 527 2023

—H 486 2024

—H 488 2025

—H 502 2026

—H 496 2027

—H 496 2028

—H 495 2029

—H 524 2030

—H 524 2031

—H 510 2032

—H 510

TABLE 212

Example R1 R2 MS(M + 1) 2033

—H 512 2034

—H 498 2035

—H 482 2036

—H 499 2037

—H 512 2038

—H 456 2039

—H 500 2040

—H 482 2041

—H 496 2042

—H 486 2043

—CH₃ 510 2044

—CH₃ 524 2045

—CH₃ 525 2046

—H 510

TABLE 213

Example R1 MS(M + 1) 2047

456 2048

486 2049

499 2050

472 2051

513 2052

482 2053

474 2054

488 2055

472 2056

500 2057

498 2058

470

TABLE 214

Example R1 MS(M + 1) 2059

486 2060

484 2061

484 2062

498 2063

486 2064

513 2065

500 2066

500 2067

527 2068

514 2069

528 2070

513 2071

485

TABLE 215

Example R1 MS(M + 1) 2072

523 2073

483 2074

477 2075

469 2076

467 2077

495 2078

556 2079

513 2080

552 2081

494

TABLE 216

Example R1 MS(M + 1) 2082

557 2083

591 2084

591 2085

571 2086

571 2087

575 2088

510 2089

508 2090

479 2091

479

TABLE 217

Example R1 MS(M + 1) 2092

481 2093

508 2094

495 2095

509 2096

495 2097

557 2098

508 2099

495 2100

540

TABLE 218

Example R1 MS(M + 1) 2101

564 2102

550 2103

481 2104

494 2105

499 2106

527 2107

550 2108

545 2109

575

TABLE 219

Example R1 MS(M + 1) 2110

570 2111

563 2112

493 2113

522 2114

523 2115

480 2116

557 2117

520 2118

533

TABLE 220

Example R1 MS(M + 1) 2119

560 2120

481 2121

543 2122

542 2123

542

TABLE 221

Example R1 R2 MS(M + 1) 2124 —CH₃ -cyclo-C₆H₁₁ 493 2125 —H -cyclo-C₆H₁₁ 479 2126 —CH₂CH₂OH —CH₂CH₂OH 485 2127 —CH₃ —CH₂CH₂N(CH₃)₂ 482 2128 —H —C₄H₆ 453 2129 —H -cyclo-C₃H₅ 437 2130 —H —CH₂C₆H₅ 487 2131 —CH₃ —CH₂C₆H₅ 501 2132 —C₂H₅ —CH(CH₃)₂ 467 2133 —H —CH₃ 411 2134 —H —C₂H₅ 425 2135 —H —C₃H₇ 439 2136 —H —CH₂CH(CH₃)₂ 453 2137 —H —CH₂CH₂OCH₃ 455 2138 —H —CH₂CH₂OC₂H₅ 469 2139 —H —(CH₂)₂OC₆H₅ 517 2140 —H -cyclo-C₅H₉ 465 2141 —H —CH₂-cyclo-C₆H₁₁ 493 2142 —H —CH(CH₃)C₆H₅ 501 2143 —H —CH₂CONH₂ 454

TABLE 222

Example R1 R2 MS(M + 1) 2144 —H —CH(CH₃)₂ 439 2145 —C₂H₅ —C₂H₅ 453 2146 —H —(CH₂)₅OH 483 2147 —H —CH₂CCH 435 2148 —CH₃ —CH(CH₃)₂ 453 2149 —H —CH₂C(CH₃)₃ 467 2150 —H —CH₂CH₂N(CH₃)₂ 468 2151 —H —CH(CONH₂)₂ 497 2152 —CH₃ —CH₂-cyclo-C₃H₅ 465 2153 —CH₃ —(CH₂)₂N(C₂H₅)₂ 510 2154 —H —CH₂CF₃ 479 2155 —H —NHCH₂CF₃ 494 2156 —CH₃ —CH₃ 425 2157 —H —CH₂CH(OCH₃)₂ 485 2158 —H —(CH₂)₃OCH(CH₃)₂ 497 2159 —H —CH(C₂H₅)₂ 467 2160 —H —CH₂CN 436 2161 —H —(CH₂)₂OCH(CH₃)₂ 483 2162 —H —CH(C₂H₅)CH₂OCH₃ 483 2163 —H —CH₂CH₂F 443 2164 —H —CH₂CONHCH₃ 468 2165 —H —(CH₂)₂SCH₃ 471 2166 —H —CH₂CHF₂ 461 2167 —CH₃ —(CH₂)₂O(CH₂)₂NHCH₃ 512

TABLE 223

Example R1 R2 MS(M + 1) 2168 —CH₃

508 2169 —H

515 2170 —H

521 2171 —H

521 2172 —H

521 2173 —H

488 2174 —H

488 2175 —H

488 2176 —H

477 2177 —CH₃

536

TABLE 224

MS Example R1 R2 (M + 1) 2178 —CH₃

531 2179 —H

451 2180 —H

517 2181 —H

517 2182 —H

555 2183 —H

571 2184 —H

531 2185 —H

552 2186 —H

495 2187 —H

505

TABLE 225

MS Example R1 R2 (M + 1) 2188 —H

547 2189 —H

501 2190 —H

505 2191 —H

496 2192 —H

544 2193 —H

481 2194 —H

468 2195 —H

517 2196 —H

508

TABLE 226

MS Example R1 R2 (M + 1) 2197 —H

508 2198 —H

494 2199 —H

510 2200 —H

453 2201 —H

467 2202 —H

555 2203 —H

537 2204 —H

527 2205 —H

527 2206 —H

493

TABLE 227

Example R1 R2 MS(M + 1) 2207 —H

556 2208 —H

555 2209 —H

555 2210 —C₂H₅

479 2211 —H

522 2212 —H

481 2213 —H

503 2214 —H

483 2215 —H

497

TABLE 228

MS Example R1 R2 (M + 1) 2216 —H

491 2217 —H

491 2218 —H

490 2219 —H

519 2220 —H

505 2221 —H

505 2222 —H

507 2223 —H

493

TABLE 229

MS Example R1 R2 (M + 1) 2224 —H

477 2225 —H

494 2226 —H

529 2227 —H

451 2228 —H

495 2229 —H

505 2230 —H

519 2231 —H

519 2232 —H

519

TABLE 230

MS Example R1 R2 (M + 1) 2233 —H

537 2234 —H

543 2235 —H

513 2236 —H

513 2237 —H

502 2238 —H

506

TABLE 231

Example R1 MS(M + 1) 2239 -2-PYRIDYL 517 2240 -3-PYRIDYL 517 2241 -4-PYRIDYL 517 2242 -2-FURYL 506 2243 -2-THIENYL 522 2244 -3-FURYL 506 2245 -3-THIENYL 522 2246 —CH₃ 454 2247 —C₂H₅ 468 2248 —C₃H₇ 482 2249 —CH(CH₃)₂ 482 2250 -cyclo-C₃H₅ 480 2251 -cyclo-C₅H₉ 508 2252 -cyclo-C₆H₁₁ 522 2253 —CH₂-cyclo-C₃H₅ 494 2254 —CH₂-cyclo-C₆H₁₁ 536 2255 —CH₂OCH₃ 484 2256 —CH₂N(CH₃)₂ 497 2257 —(CH₂)₃N(CH₃)₂ 525 2258 —(CH₂)₂N(C₂H₅)₂ 539 2259 —CH₂NHCHO 497 2260 —CH₂N(CH₂CH₂OH)₂ 557 2261 —CH₂N(CH₃)CO₂C(CH₃)₃ 583 2262 —(CH₂)₃NHCO₂C(CH₃)₃ 597 2263 —CH₂NHCH₃ 483 2264 —(CH₂)₃NH₂ 497 2265 —CH₂NHCOCH₃ 511

TABLE 232

Example R1 MS(M + 1) 2266

547 2267

551 2268

585 2269

563 2270

551 2271

533 2272

567 2273

551 2274

505

TABLE 233

Example R1 MS(M + 1) 2275

556 2276

551 2277

519 2278

535 2279

518 2280

532 2281

523 2282

534 2283

590

TABLE 234

Example R1 MS(M + 1) 2284

556 2285

589 2286

521 2287

523 2288

535 2289

520 2290

520

TABLE 235

Example R1 MS(M + 1) 2292

520 2293

521 2294

521 2295

565 2296

579 2297

523 2298

541 2299

510 2300

524

TABLE 236

MS Example R1 (M + 1) 2301

623 2302

609 2303

595 2304

595 2305

623 2306

623 2307

523 2308

509 2309

495

TABLE 237

Example R1 MS(M + 1) 2310

495 2311

523 2312

523

TABLE 238

Example R1 MS(M + 1) 2313

545 2314

531 2315

531 2316

531 2317

536 2318

536 2319

522 2320

2321

543

TABLE 239

Example R1 MS(M + 1) 2322

543 2323

563 2324

543 2325

556 2326

551 2327

532 2328

582 2329

520 2330

522

TABLE 240

Example R1 MS(M + 1) 2331

538 2332

532 2333

637 2334

651 2335

673 2336

537 2337

551 2338

573

TABLE 241

Example R1 MS(M + 1) 2339 -2-PYRIDYL 549 2340 —C₄H₉ 528 2341 —CH(CH₃)₂ 514 2342 —CH₂CH₂N(CH₃)₂ 543 2343 -4-PYRIDYL 549 2344 —C₆H₅ 548 2345 —C₃H₇ 514 2346 —CH₃ 486 2347 -3-PYRIDYL 549 2348 —C₆H₁₃ 556 2349 —C₂H₅ 500 2350 —CH₂CH₂OH 516 2351 —COCH₃ 514 2352 -cyclo-C₆H₁₁ 554 2353 —SO₂C₂H₅ 564

TABLE 242

Example R1 MS(M + 1) 2354

563 2355

563 2356

563 2357

550 2358

569 2359

634 2360

550 2361

566 2362

577

TABLE 243

Example R1 MS(M + 1) 2363

577 2364

583 2365

555 2366

540

TABLE 244

Example R1 MS(M + 1) 2367 —OCH₃ 501 2368 -cyclo-C₆H₁₁ 553 2369 —C₆H₅ 547 2370 —OCH₂C₆H₅ 577 2371 —OC₆H₅ 563 2372 —OH 487 2373 —CONH₂ 514 2374 —CH₂OH 501 2375 —C₂H₅ 499 2376 —NHCOCH₃ 528 2377 —COC₆H₅ 575 2378 -2-PYRIDYL 548

TABLE 245

Example R1 MS(M + 1) 2379

554 2380

578 2381

578 2382

556 2383

564 2384

564

TABLE 246

Example R1 MS(M + 1) 2385

485 2386

502 2387

525 2388

489 2389

475 2390

511 2391

539 2392

547 2393

576

TABLE 247

Example R1 MS(M + 1) 2394

519 2395

563 2396

558 2397

519 2398

505 2399

500 2400

548 2401

563 2402

487

TABLE 248

Example R1 MS(M + 1) 2403

515 2404

577 2405

473 2406

546 2407

570 2408

505 2409

533 2410

486 2411

545

TABLE 249

Example R1 MS(M + 1) 2412

542 2413

526 2414

568 2415

539 2416

578 2417

487 2418

583 2419

549 2420

554

TABLE 250

Example R1 MS(M + 1) 2421

548 2422

546 2423

553 2424

561 2425

526 2426

443

TABLE 251

Example R1 R2 MS(M + 1) 2427 -cyclo-C₆H₁₁ —CH₃ 499 2428 —H -cyclo-C₆H₁₁ 485 2429 —H —CH(CH₃)₂ 445 2430 —C₄H₉ —C₄H₉ 515 2431 —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ 515 2432 —CH₂CH₂OH —CH₂CH₂OH 491 2433 —CH₂CH₂OH —C₂H₅ 475 2434 —C₆H₁₃ —C₆H₁₃ 571 2435 —CH₂CH₂N(CH₃)₂ —CH₃ 488 2436 -cyclo-C₆H₁₁ —CH₂CH₂OH 529 2437 —CH₂CH₂OCH₃ —CH₂CH₂OCH₃ 519 2438 —(CH₂)₃N(CH₃)₂ —(CH₂)₃N(CH₃)₂ 573 2439 —(CH₂)₃N(C₂H₅)₂ —CH₃ 530 2440 —CH₂CH═CH₂ -cyclo-C₅H₉ 511 2441 —C₂H₅ —C₂H₅ 459 2442 —H —C(CH₃)₃ 459 2443 —H -cyclo-C₃H₅ 443 2444 —H -cyclo-C₇H₁₃ 499 2445 —H —CH₂C₆H₅ 493 2446 —C₃H₇ —(CH₂)₃C₆H₅ 563 2447 —CH₂CONHCH₃ —CH₂C₆H₅ 564 2448 —CH₂C₆H₅ -cyclo-C₆H₁₁ 575 2449 —(CH₂)₂C₆H₅ —CH₃ 521 2450 —CH₂C₆H₅ —CH₃ 507 2451 —CH₂CH₂N(CH₃)₂ —CH₂C₆H₅ 564 2452 —CH₂C₆H₅ —C₅H₁₁ 563

TABLE 252

Example R1 R2 MS(M + 1) 2453 —CH₂C₆H₅ —CH₂C₆H₅ 583 2454 —CH₂C₆H₅ —C₂H₅ 521 2455 —CH₂C₆H₅ —CH(CH₃)₂ 535 2456 —CH₂CH₂CN —CH₂C₆H₅ 546 2457 —(CH₂)₂OC₆H₅ —CH₃ 537 2458 -cyclo-C₆H₁₁ —C₂H₅ 513 2459 —CH(CH₃)₂ —C₂H₅ 473 2460 —H —C₂H₅ 431 2461 —H —CH₂CH(CH₃)₂ 459 2462 —H —CH₂CH₂OCH₃ 461 2463 —C₂H₅ —C₄H₉ 487 2464 —H —CH₂CH₂OC₂H₅ 475 2465 —H —(CH₂)₃OC₂H₅ 489 2466 —CH₂C₆H₅ —C₆H₅ 569 2467 —C₆H₅ —C₂H₅ 507 2468 —C₆H₅ -cyclo-C₆H₁₁ 561 2469 —CH₂CH₂CN —C₆H₅ 532 2470 -2-PYRIDYL —C₂H₅ 508 2471 —H —C₆H₅ 479 2472 —H -3-PYRIDYL 480 2473 —H -2-PYRIDYL 480 2474 —H -4-PYRIDYL 480 2475 —C₆H₅ —CH₃ 493 2476 —H —CH₂-cyclo-C₆H₁₁ 499 2477 —H —(CH₂)₃C₆H₅ 521 2478 —H —(CH₂)₂NHCOCH₃ 488 2479 —H —(CH₂)₅OH 489

TABLE 253

Example R1 R2 MS(M + 1) 2480 —H —(CH₂)₂C₆H₅ 507 2481 —H —CH₂CONH₂ 460 2482 —H —CH₂CCH 441 2483 —C₅H₁₁ —CH₃ 487 2484 —H —(CH₂)₂CH(CH₃)₂ 473 2485 —H —CH₂C(CH₃)₃ 473 2486 —H —CH₂CH₂N(CH₃)₂ 474 2487 —CH₂C₆H₅ —(CH₂)₃OH 551 2488 —CH₃ —CH₂-cyclo-C₃H₅ 471 2489 —H —CH₂CF₃ 485 2490 —H —NHCH₂CF₃ 500 2491 —CH₃ —CH₃ 431 2492 —H —(CH₂)₃OCH(CH₃)₂ 503 2493 —H —CH₂CH₂C(CH₃)₃ 487 2494 —H —CH₂CN 442 2495 —H —(CH₂)₃OCH₃ 475 2496 —H —(CH₂)₂OCH(CH₃)₂ 489 2497 —H —CH₂CH₂CN 456 2498 —H —CH₂CONHCH₃ 474 2499 —H —(CH₂)SCH₃ 477 2500 —H —CH₂CHF₂ 467 2501 —H —CH₂CH₂OH 447 2502 —H —C₆H₁₃ 487 2503 —CH₂CON(CH₃)₂ —CH₃ 502 2504 —CH₂C₆H₅ —CH₂CH₂OCH₃ 551 2505 —H —(CH₂)₂NHCONH₂ 489

TABLE 254

Example R1 R2 MS(M + 1) 2506

—CH₃ 522 2507

—CH₃ 514 2508

—C₂H₅ 529 2509

—H 494 2510

—H 494 2511

—H 494 2512

—H 483 2513

—C₂H₅ 536 2514

—CH₃ 542 2515

—C₂H₅ 547

TABLE 255

Example R1 R2 MS(M + 1) 2516

—CH₃ 564 2517

—C₂H₅ 522 2518

—H 457 2519

—H 485 2520

—CH₃ 507 2521

—H 509 2522

—H 521 2523

—H 529 2524

—H 544 2525

—H 519

TABLE 256

Example R1 R2 MS(M + 1) 2526

—H 530 2527

—H 530 2528

—H 571 2529

—H 518 2530

—H 558 2531

—H 486 2532

—H 552 2533

—H 471 2534

—H 562

TABLE 257

Example R1 R2 MS(M + 1) 2535

—H 572 2536

—H 536 2537

—H 523 2538

—H 534 2539

—H 570 2540

—H 540 2541

—H 533 2542

—H 519 2543

—H 487

TABLE 258

Example R1 R2 MS(M + 1) 2544

—H 497 2545

—H 501 2546

—H 545 2547

—H 535 2548

—H 545 2549

—H 546 2550

—H 530 2551

—H 483

TABLE 259

Example R1 R2 MS(M + 1) 2552

—H 562 2553

—H 532 2554

—H 545 2555

—H 560 2556

—H 559 2557

—H 559 2558

—H 546 2559

—H 511 2560

—H 530

TABLE 260

Example R1 R2 MS(M + 1) 2561

—H 508 2562

—H 514 2563

—H 514 2564

—H 500 2565

—H 514 2566

—H 516 2567

—H 530 2568

—H 561 2569

—H 543 2570

—H 546

TABLE 261

Example R1 R2 MS(M + 1) 2571

—H 533 2572

—H 499 2573

—H 528 2574

—H 487 2575

—H 509 2576

—H 508 2577

—H 508 2578

—H 497 2579

—H 497 2580

—H 496

TABLE 262

Example R1 R2 MS(M + 1) 2581

—H 525 2582

—H 511 2583

—H 511 2584

—H 513 2585

—H 499 2586

—H 483 2587

—H 500 2588

—H 513 2589

—H 535 2590

—H 457

TABLE 263

Example R1 R2 MS(M + 1) 2591

—H 527 2592

—H 554 2593

—H 549 2594

—H 519 2595

—H 519 2596

—H 497 2597

—H 546 2598

—H 497 2599

—H 528 2600

—H 487

TABLE 264

Example R1 R2 MS(M + 1) 2601

—H 575 2602

—CH₃ 511 2603

—CH₃ 525 2604

—CH₃ 557 2605

—CH₃ 528 2606

—CH₃ 544 2607

—H 547 2608

—CH₃ 526 2609

—CH₃ 564

TABLE 265

Example R1 R2 MS(M + 1) 2610

—CH₃ 574 2611

—CH₃ 547 2612

—H 511 2613

—CH₃ 561 2614

—CH₃ 564 2615

—H 512 2616

—H 515 2617

—CH₃ 560 2618

—H 566

TABLE 266

Example R1 R2 MS(M + 1) 2619

—H 573 2620

—CH₃ 571 2621

—CH₃ 584 2622

—CH₃ 587 2623

—H 560 2624

—H 547 2625

—H 549

TABLE 267

Example R1 MS(M + 1) 2626 -2-PYRIDYL 544 2627 —C₄H₉ 523 2628 —CH(CH₃)₂ 509 2629 —CH₂CH₂N(CH₃)₂ 538 2630 -4-PYRIDYL 544 2631 —C₆H₅ 543 2632 —C₃H₇ 509 2633 —CH₂CH₂OCH₃ 525 2634 —CH₃ 481 2635 -3-PYRIDYL 544 2636 —C₆H₁₃ 551 2637 —C₂H₅ 495 2638 —CH₂CH₂OH 511 2639 —COCH₃ 509 2640 -cyclo-C₆H₁₁ 549 2641 —SO₂C₂H₅ 559

TABLE 268

Example R1 MS(M + 1) 2642

558 2643

558 2644

558 2645

545 2646

564 2647

629 2648

545 2649

551 2650

561

TABLE 269

Example R1 MS(M + 1) 2651

572 2652

572 2653

578 2654

550 2655

535

TABLE 270

Example R1 MS(M + 1) 2656 —OCH₃ 496 2657 -cyclo-C₆H₁₁ 548 2658 —C₆H₅ 542 2659 —OCH₂C₆H₅ 572 2660 —OC₆H₅ 558 2661 —OH 482 2662 —CONH₂ 509 2663 —C₂H₅ 494 2664 —NHCOCH₃ 523 2665 —COC₆H₅ 570 2666 -2-PYRIDYL 543

TABLE 271

Example R1 MS(M + 1) 2667

549 2668

573 2669

573 2670

551 2671

559 2672

559

TABLE 272

Example R1 MS(M + 1) 2673

480 2674

520 2675

484 2676

470 2677

506 2678

534 2679

542 2680

571 2681

514 2682

558

TABLE 273

Example R1 MS(M + 1) 2683

553 2684

514 2685

500 2686

495 2687

543 2688

558 2689

510 2690

572 2691

468

TABLE 274

Example R1 MS(M + 1) 2692

541 2693

565 2694

500 2695

528 2696

481 2697

540 2698

537 2699

521 2700

563 2701

534

TABLE 275

Example R1 MS(M + 1) 2702

573 2703

482 2704

578 2705

544 2706

549 2707

543 2708

541 2709

548

TABLE 276

Example R1 MS(M + 1) 2710

556 2711

521 2712

438

TABLE 277

Example R1 R2 MS(M + 1) 2713 -cyclo-C₆H₁₁ —CH₃ 494 2714 —H —CH(CH₃)₂ 440 2715 —C₄H₉ —C₄H₉ 510 2716 —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ 510 2717 —CH₂CH₂OH —CH₂CH₂OH 486 2718 —C₆H₁₃ —C₆H₁₃ 566 2719 —CH₂CH₂N(CH₃)₂ —CH₃ 483 2720 —CH₂CH₂OCH₃ —CH₂CH₂OCH₃ 514 2721 —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ 568 2722 —(CH₂)₃N(C₂H₅)₂ —CH₃ 525 2723 —CH₂CH═CH₂ -cyclo-C₅H₉ 506 2724 —H —C₄H₉ 454 2725 —H -cyclo-C₃H₅ 438 2726 —H -cyclo-C₇H₁₃ 494 2727 —H —CH₂C₆H₅ 488 2728 —C₃H₇ —(CH₂)₃C₆H₅ 558 2729 —CH₂CONHCH₃ —CH₂C₆H₅ 559 2730 —CH₂C₆H₅ -cyclo-C₆H₁₁ 570 2731 —(CH₂)₂C₆H₅ —CH₃ 516 2732 —CH₂C₆H₅ —CH₃ 502 2733 —CH₂CH₂N(CH₃)₂ —CH₂C₆H₅ 559 2734 —CH₂C₆H₅ —C₅H₁₁ 558 2735 —CH₂C₆H₅ —CH₂C₆H₅ 578 2736 —CH₂C₆H₅ —C₂H₅ 516 2737 —CH₂C₆H₅ —CH(CH₃)₂ 530 2738 —CH₂CH₂CN —CH₂C₆H₅ 541 2739 —(CH₂)₂OC₆H₅ —CH₃ 532 2740 -cyclo-C₆H₁₁ —C₂H₅ 508

TABLE 178

Example R1 R2 MS(M + 1) 2741 —CH(CH₃)₂ —C₂H₅ 468 2742 —H —C₂H₅ 426 2743 —H —C₃H₇ 440 2744 —H —CH₂CH₂OCH₃ 456 2745 —CH₂-cyclo-C₆H₁₁ —C₂H₅ 522 2746 —C₂H₅ —C₄H₉ 482 2747 —H -1-CH₃-CYCLOHEXYL 494 2748 —H —(CH₂)₂OC₆H₅ 518 2749 —CH₂C₆H₅ —C₆H₅ 564 2750 —C₆H₅ —CH₂CH₂OH 518 2751 —C₆H₅ —C₂H₅ 502 2752 —CH₂CH₂CN —C₆H₅ 527 2753 -2-PYRIDYL —C₂H₅ 503 2754 —H —C₆H₅ 474 2755 —H -3-PYRIDYL 475 2756 —H -2-PYRIDYL 475 2757 —H -4-PYRIDYL 475 2758 —C₆H₅ —CH₃ 488 2759 —H —CH₂-cyclo-C₆H₁₁ 494 2760 —H —(CH₂)₃C₆H₅ 516 2761 —H —(CH₂)₂C₆H₅ 502 2762 —H —CH₂CONH₂ 455 2763 —H —CH₂CCH 436 2764 —C₅H₁₁ —CH₃ 482 2765 —CH(CH₃)₂ —CH₃ 454 2766 —H —(CH₂)₂CH(CH₃)₂ 468 2767 —H —CH₂C(CH₃)₃ 468 2768 —H —CH₂CH₂N(CH₃)₂ 469

TABLE 279

Example R1 R2 MS(M + 1) 2769 —CH₂C₆H₅ —(CH₂)₃OH 546 2770 —CH₃ —CH₂-cyclo-C₃H₅ 466 2771 —H —CH₂CF₃ 480 2772 —H —NHCH₂CF₃ 495 2773 —CH₃ —CH₃ 426 2774 —H —(CH₂)₃OCH(CH₃)₂ 498 2775 —H —CH₂CH₂C(CH₃)₃ 482 2776 —H —CH₂CN 437 2777 —H —(CH₂)₃OCH₃ 470 2778 —H —(CH₂)₂OCH(CH₃)₂ 484 2779 —H —CH₂CH₂CN 451 2780 —H —CH₂CONHCH₃ 469 2781 —H —(CH₂)SCH₃ 472 2782 —H —CH₂CHF₂ 462 2783 —H —C₆H₁₃ 482 2784 —CH₂CON(CH₃)₂ —CH₃ 497 2785 —CH₂C₆H₅ —CH₂CH₂OCH₃ 546 2786 —H —(CH₂)₂NHCONH₂ 484

TABLE 280

Example R1 R2 MS(M + 1) 2787

—CH₃ 517 2788

—CH₃ 509 2789

—C₂H₅ 524 2790

—H 489 2791

—H 489 2792

—H 489 2793

—H 478 2794

—C₂H₅ 531 2795

—CH₃ 537 2796

—C₂H₅ 542

TABLE 281

Example R1 R2 MS(M + 1) 2797

—CH₃ 559 2798

—C₂H₅ 517 2799

—H 452 2800

—H 480 2801

—CH₃ 536 2802

—CH₃ 502 2803

—H 508 2804

—H 504 2805

—H 516 2806

—H 524 2807

—H 539

TABLE 282

Example R1 R2 MS(M + 1) 2808

—H 514 2809

—H 525 2810

—H 525 2811

—H 566 2812

—H 513 2813

—H 553 2814

—H 481 2815

—H 476 2816

—H 519 2817

—H 547

TABLE 283

Example R1 R2 MS(M + 1) 2818

—H 465 2819

—H 466 2820

—H 479 2821

—H 557 2822

—H 567 2823

—H 531 2824

—H 518 2825

—H 529 2826

—H 565

TABLE 284

Example R1 R2 MS(M + 1) 2827

—H 535 2828

—H 514 2829

—H 492 2830

—H 525 2831

—H 496 2832

—H 493 2833

—H 540 2834

—H 530 2835

—H 540

TABLE 285

Example R1 R2 MS(M + 1) 2836

—H 541 2837

—H 525 2838

—H 478 2839

—H 476 2840

—H 495 2841

—H 465 2842

—H 557 2843

—H 527 2844

—H 540

TABLE 286

Example R1 R2 MS(M + 1) 2845

—HH 555 2846

—H 554 2847

—H 554 2848

—H 541 2849

—H 506 2850

—H 525 2851

—H 503 2852

—H 509 2853

—H 509 2854

—H 495

TABLE 287

Example R1 R2 MS(M + 1) 2855

—H 509 2856

—H 511 2857

—H 525 2858

—H 556 2859

—H 538 2860

—H 541 2861

—H 528 2862

—H 494 2863

—H 523 2864

—H 482

TABLE 288

Example R1 R2 MS(M + 1) 2865

—H 504 2866

—H 503 2867

—H 503 2868

—H 492 2869

—H 492 2870

—H 491 2871

—H 520 2872

—H 506 2873

—H 506 2874

—H 508

TABLE 289

Example R1 R2 MS(M + 1) 2875

—H 494 2876

—H 478 2877

—H 495 2878

—H 508 2879

—H 530 2880

—H 452 2881

—H 522 2882

—H 495 2883

—H 549 2884

—H 544 2885

—H 514

TABLE 290

Example R1 R2 MS(M + 1) 2886

—H 514 2887

—H 492 2888

—H 541 2889

—H 492 2890

—H 482 2891

—H 570 2892

—CH₃ 506 2893

—CH₃ 520 2894

—CH₃ 552 2895

—CH₃ 523 2896

—CH₃ 539

TABLE 291

Example R1 R2 MS(M + 1) 2897

—H 542 2898

—CH₃ 521 2899

—CH₃ 559 2900

—CH₃ 569 2901

—CH₃ 542 2902

—H 506 2903

—CH₃ 556 2904

—CH₃ 559 2905

—H 507

TABLE 292

Example R1 R2 MS(M + 1) 2906

—H 510 2907

—CH₃ 555 2908

—H 561 2909

—H 568 2910

—CH₃ 566 2911

—CH₃ 579 2912

—CH₃ 582 2913

—H 544

TABLE 293

Crystal form Melting (Recrystalization Point Example R1 R2 R3 R4 R5 solvent) (° C.) Salt 2914 —CH₃ —H

—H —OCH₃ White powder (Ethyl acetate) 230.0 (dec) Hydrochloride 2915 —CH₃ —H

—H —OCH₃ 2916 —CH₃ —H

—H —OCH₃ White powder (Ethyl acetate) 235.0 (dec) Hydrochloride 2917 —CH₃ —H

—H —OCH₃ White powder (Ethyl acetate) 227.0 (dec) Hydrochloride 2918 —CH₃ —H

—H —OCH₃ White powder (Ethyl acetate) 240.0 (dec) Hydrochloride 2919 —OCH₃ —H

—H —OCH₃ White powder (Ethyl acetate) 211.0- 213.5 Hydrochloride

TABLE 294

Crystal form Melting (Recrystalization Point Example R1 R2 R3 R4 R5 solvent) (° C.) Salt 2920 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 207.5- 210.0 Hydrochloride 2921 —OCH₃ —H

—H —CH₃ White powder (Ethanol/ ethyl acetate) 247.0 (dec) — 2922 —CH₃ —H —CONHCH₃ —H —OC₃H₇ White powder (Ethanol) 2923 —OCH₃ —H

—H —CH₃ Hydrochloride 2924 —OCH₃ —H

—H —CH₃ White powder (Ethyl acetate) 248.5- 257.5 Hydrochloride

TABLE 295

Example R1 R2 R3 R4 R5 NMR Salt 2925 —CH₃ —H

—H —OCH₃ ¹H-NMR (CDCl3) δ ppm: 1.36-1.65 (4H, m), 1.88-2.11 (3H, m), 2.25 (3H, s), 2.47 (3H, s), 2.60-2.82 (8H, m), 3.12-3.29 (4H, m), 3.47-3.63 (2H, m), 3.82 (3H, s), 3.93 (2H, t, J = 6.4Hz), 6.34 (1H, d, J = 2.7 Hz), 6.40 (1H, d, J = 2.7 Hz), 6.90(1H, d, J = 7.1 Hz), 7.21-7.34 (1H, m), 7.40 (2H, dd, J = 5.5 Hz, 9.9 Hz), 7.55 (1H, d, J = 8.0 Hz). — 2926 —CH₃ —H

—H —OCH₃ ¹H-NMR (CDCl3) δ ppm: 1.48 (9H, s), 1.67-1.92 (4H, m), 1.95-2.11 (2H, m), 2.25 (3H, s), 2.61-2.87 (12H, m), 3.11-3.28 (4H, m), 3.54-3.70 (2H, m), 3.83 (3H, s), 3.94 (2H, t, J = 6.3 Hz), 6.34 (1H, d, J = 2.6 Hz), 6.39 (1H, d, J = 2.6 Hz), 6.90 (1H, d, J = 6.9 Hz), 7.17-7.34(1H, m), 7.35-7.47 (2H, m), 7.55(1H, d, J = 8.0 Hz). — 2927 —CH₃ —H

—H —OCH₃ ¹H-NMR (CDCl3) δ ppm: 1.96-2.11 (2H, m), 2.27 (3H, s), 2.57 (4H, t, J = 6.0 Hz), 2.64-2.84 (6H, m), 3.13-3.27 (14H, m), 3.51 (4H, t, J = 6.0 Hz), 3.84 (3H, s), 3.96 (2H, t, J = 6.4 Hz), 6.38 (1H, d, J = 2.7 Hz), 6.20 (1H, d, J = 2.7 Hz), 6.90 (1H, d, J = 7.5 Hz), 7.21-7.32 (1H, m), 7.40 (2H, dd, J = 5.5 Hz, 10.0 Hz), 7.55(1H, d, J = 8.1 Hz). — 2928 —CH₃ —H

—H —OCH₃ ¹H-NMR (CDCl3) δ ppm: 1.83-1.95 (4H, m), 1.95-2.10 (2H, m), 2.25 (3H, s), 2.61-2.81 (6H, m), 3.07-3.28 (14H, m) 3.82 (3H, s), 3.93 (2H, t, J = 6.5 Hz), 6.30-6.43 (2H, m), 6.90(1H, d, J = 7.5 Hz), 7.29-7.34 (1H, m), 7.41 (2H, dd, J = 6.0 Hz, 10.0 Hz ), 7.55 (1H, d, J = 7.9 Hz). —

TABLE 296

Crystal form Melting Point Example R1 R2 R3 R4 R5 (Recrystalization solvent) (° C.) Salt 2929 —OCH₃ —H —CONH₂ —H —CH₃ White powder 189.0-192.5 Hydrochloride (Ethanol) 2930 —OCH₃ —H —CONHCH₃ —H —CH₃ White powder 165.5-167.0 — (Isopropyl alcohol/water)

TABLE 297

Crystal form (Recrystalization Melting Point Example R1 solvent) (° C.) Salt 2931

White powder (Ethyl acetate/ methanol) 214-217 Hydrochloride 2932

White powder (Ethyl acetate/ methanol) 218-222 1/2 fumarate 2933

Colorless needle- form crystal (Ethanol) 195-196 — 2934

White powder (Ethyl acetate) 145-146 — 2935

White powder (Ethanol/ ethyl acetate) 219-221 Dihydrochloride 2936

White powder (Ethyl acetate) 162-164 — 2937

White powder (Ethanol/ether) 208.5-209.5 Dihydrochloride 2938

White powder (n-hexane/ ethyl acetate) 137-139 — 2939

White powder (Ethanol) 137-139 — 2940

White powder (Ethyl acetate) 163-165 — 2941

White powder (Ethyl acetate) 196-199 —

TABLE 298

Crystal form Melting (Recrystalization Point Example R1 solvent) (°C.) Salt 2942

White powder (Ethyl acetate) 197-199 — 2943

White powder (Ethanol) 232-233 Dihydrochloride 2944

White powder (Ethanol/ether) 255-257 Hydrochloride 2945

White powder (Ethanol) 169.5-172.5 — 2946

White powder (Ethanol) 195.0-196.5 — 2947

White powder (Ethyl acetate/ isopropyl ether) 151.5-153.5 — 2948

White powder (Ethyl acetate) 235.0 (dec) Hydrochloride 2949

2950

White powder (Ethyl acetate) 224.0-227.5 Hydrochloride 2951

White powder (Ethyl acetate/ isopropyl ether) 175.0-178.5 —

TABLE 299

Crystal form (Recrystalization Melting Point Example R1 solvent) (°C.) Salt 2952

White powder (Ethyl acetate) 169.0-173.0 Trihydrochloride 2953

2954

White powder (Ethyl acetate) 210.0-217.0 Dihydrochloride 2955

White powder (Ethyl acetate) 181.0-188.0 Dihydrochloride 2956

White powder (Ethanol/ethyl acetate) 163.5-167.0 Hydrochloride 2957

White powder (Ethyl acetate/ether) 172.5-176.5 Hydrochloride 2958

White powder (Ethyl acetate/ether) 145.0-151.0 Dihydrochloride 2959

White powder (Ethanol/ethyl acetate) 144.0-150.0 Dihydrochloride

TABLE 300

Crystal form (Recrystalization Melting Point Example R1 solvent) (°C.) Salt 2960

White powder (Ethyl acetate/ether) 177-182 Dihydrochloride 2961

White powder (Ethyl acetate/ether) 198-201 Hydrochloride 2962

White powder (Ethyl acetate/ether) 195-200 Hydrochloride 2963

White powder (Ethyl acetate/ether) 215-218 Hydrochloride 2964

White powder (Ethyl acetate/ether) 152-157 Hydrochloride 2965

White powder (Ethyl acetate/ether) 158-161 Hydrochloride 2966

White powder (Ethyl acetate/ether) 168-172 Hydrochloride 2967

White powder (Ethyl acetate) 178.5-181.5 — 2968

White powder (Ethyl acetate) 228.0 (dec) Hydrochloride

TABLE 301

Example R1 NMR Salt 2969

¹H-NMR (DMSO-d6) δ ppm: 1.95-2.10 (2H, m), 2.85- 2.95 (2H, m), 3.00-3.15 (4H, m), 3.15-3.30 (4H, m), 4.41 (2H, t, J = 5.8 Hz), 6.89 (1H, d, J = 5.0 Hz), 7.15 (1H, s), 7.26 (1H, t, J = 7.9 Hz), 7.43 (1H, d, J = 5.5 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 5.5 Hz), 8.73 (1H, s). — 2970

¹H-NMR (CDCl₃) δ ppm: 1.72-1.98 (4H, m), 2.30- 2.46 (1H, m), 2.46-2.58 (2H, m), 2.62-2.77 (5H, m), 2.80 (3H, d, J = 5.1 Hz), 3.04-3.29 (5H, m), 3.38-3.55 (2H, m), 3.83-4.04 (2H, m), 6.90 (1H, dd, J = 0.5 Hz, 7.6 Hz), 7.22-7.34 (1H, m), 7.34-7.47 (2H, m), 7.55 (1H, d, J = 8.0 Hz), 7.63(1H, br). 2971

¹H-NMR (CDCl₃) δ ppm: 1.46 (9H, s), 1.70-1.89 (2H, m), 1.90-2.17 (1H, m), 2.44-2.60 (2H, m), 2.62-2.75 (4H, m), 2.81 (3H, d, J = 4.7 Hz), 3.09-3.26 (4H, m), 3.39-3.57 (4H, m), 3.93-4.21 (1H, m), 4.21-4.46 (1H, m), 6.65-6.95 (1H, br), 6.90 (1H, d, J = 7.0 Hz), 7.20-7.34 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J = 8.0 Hz).

Example R1 MS(M + 1) Salt 2972

440 Hydrochloride 2973

360 Maleate

TABLE 302

Crystal form Melting Point Example R1 (Recrystalization solvent) (°C) Salt 2974

White powder (Ethyl acetate/ether) 215.5-216.5 Hydrochloride 2975

2976

White powder (Ethyl acetate/ isopropyl ether) 132.5-135.0 — 2977

White powder (2-proparol water) 180.0-182.0 — 2978

White powder (Ethyl acetate) 216.0-220.2 Hydrochloride 2979

White powder (Ethyl acetate) 203.0-207.0 Hydrochloride 2980

White powder (Ethyl acetate/ isopropyl ether) 146.5-148.0 — 2981

White powder (Ethyl acetate) 197.0-201.0 Hydrochloride 2982

White powder (Ethyl acetate/ isopropyl ether) 133.0-134.5 —

TABLE 303

Example R1 R2 R3 R4 R5 R6 MS(M + 1) 2983 —OCH₃ —H —H —H —H —CH₃ 517 2984 —H —H —CH₃ —H —H —CH₃ 501 2985 —H —H —Cl —H —H —CH₃ 521 2986 —H —SCH₃ —H —H —H —H 519 2987 —SCH₃ —H —H —H —H —H 519 2988 —H —Cl —Cl —H —H —H 541 2989 —H —H —OCF₃ —H —H —H 557 2990 —H —H —H —H —H —H 473 2991 —H —H —Cl —H —H —H 507 2992 —H —H —OCH₃ —H —H —H 503 2993 —OCH₃ —H —H —H —H —H 503 2994 —H —OCH₃ —H —H —H —H 503 2995 —Cl —H —H —H —H —H 507 2996 —H —Cl —H —H —H —H 507 2997 —H —H —CH₃ —H —H —H 487 2998 —OCH₃ —H —OCH₃ —H —H —H 533 2999 —N(CH₃)₂ —H —H —H —H —H 516 3000 -1-PYRRYL —H —H —H —H —H 538 3001 —H —Cl —H —H —OCH₃ —H 537 3002 —H —OCH₃ —H —H —OCH₃ —H 533 3003 —H —OCH₃ —H —OCH₃ —H —H 533 3004 —OCH₃ —H —H —CH₃ —H —H 517 3005 —H —OCH₃ —OCH₃ —H —H —H 533 3006 —C(CH₃)═CH₂ —H —H —H —H —H 513 3007 —H —OCF₃ —H —H —H —H 557 3008 —CH₃ —H —H —H —H —H 487 3009 —H —CH₃ —H —H —H —H 487 3010 —F —H —H —H —H —H 491

TABLE 304

Example R1 R2 R3 R4 R5 R6 MS(M+1) 3011 —H —H —F —H —H —H 491 3012 —H —N(CH₃)₂ —H —H —H —H 516 3013 —H —H —N(CH₃)₂ —H —H —H 516 3014 —CF₃ —H —H —H —H —H 541 3015 —H —CF₃ —H —H —H —H 541 3016 —H —NHCOCH₃ —H —H —H —H 530 3017 —H —H —NHCOCH₃ —H —H —H 530 3018 —H —H —H —H —CN —H 498 3019 —H —H —H —CN —H —H 498 3020 —CH₃ —H —H —H —H —CH₃ 501 3021 —H —CH₃ —H —H —H —CH₃ 501 3022 —H —Cl —H —H —H —CH₃ 521 3023 —H —H —OH —H —H —CH₃ 503 3024 —CH₃ —CH3 —H —H —H —H 501 3025 —CH₃ —H —CH₃ —H —H —H 501 3026 —CH₃ —H —H —H —CH₃ —H 501 3027 —H —CH₃ —CH₃ —H —H —H 501 3028 —H —CH₃ —H —CH₃ —H —H 501 3029 —F —F —H —H —H —H 509 3030 —H —F —F —H —H —H 509 3031 —H —F —H —F —H —H 509 3032 —H —F —OCH₃ —H —H —H 521 3033 —H —OCH₃ —CH₃ —H —H —H 517 3034 —H —Cl —OCH₃ —H —H —H 537 3035 —H —Cl —CH₃ —H —H —H 521 3036 —OCH₃ —OCH₃ —H —H —H —H 533 3037 —H —Cl —OH —H —H —H 523 3038 —Cl —H —H —CH₃ —H —H 521

TABLE 305

Example R1 R2 R3 R4 R5 R6 MS(M+1) 3039 —H —CONH₂ —H —H —Cl —H 550 3040 —CH₃ —H —Br —H —CH₃ —H 579 3041 —H —H —CN —H —H —H 498 3042 —H —H —SCH₃ —H —H —H 519 3043 —H —H —CH(CH₃)₂ —H —H —H 515 3044 —H —H -2-FURYL —H —H —H 539

TABLE 306

Example R1 R2 R3 R4 R5 R6 MS(M+1) 3045 —H

—H —H —H —H 539 3046 —H

—H —H —H —H 540 3047 —H

—H —H —H —H 542 3048 —H —H

—H —H —H 554 3049 —H

—H —H —H —H 553 3050 —H —H

—H —H —H 553 3051 —H

—H —H —H —H 540

TABLE 307

Example R1 R2 MS(M+1) 3052

—H 474 3053

—H 523 3054

—H 513 3055

—H 474 3056

—H 474 3057

—H 524 3058

—H 504 3059

—H 512 3060

—H 560

TABLE 308

Example R1 R2 MS(M+1) 3061

—H 556 3062

—H 556 3063

—H 572 3064

—H 488 3065

—H 480 3066

—H 524 3067

—H 546 3068

—H 478

TABLE 309

Example R1 R2 MS(M+1) 3069

—H 556 3070

—H 528 3071

—H 564 3072

—H 534 3073

—H 513 3074

—H 491 3075

—H 506 3076

—H 492 3077

—H 529

TABLE 310

Example R1 R2 MS(M+1) 3078

—H 480 3079

—H 477 3080

—H 494 3081

—H 464 3082

—H 478 3083

—H 566 3084

—H 556 3085

—H 526

TABLE 311

Example R1 MS(M+1) 3086

553 3087

525 3088

567 3089

499 3090

497 3091

543 3092

549 3093

559

Example 3094 Synthesis of 3-amino-4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-N-ethyl-benzamide

5% palladium carbon (0.8 g) was added to an ethanol solution (30 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-N-ethyl-3-nitrobenzamide (1.0 g, 2.1 mmol) and the mixture was subjected to catalytic reduction at room temperature under normal pressure. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Water was added to the residue and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1→20:1). The purified product was concentrated under reduced pressure to obtain 3-amino-4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-N-ethyl-benzamide (0.78 g, 83% yield) as yellow amorphous solid.

¹H-NMR (CDCl₃) δppm: 1.23 (3H, t, J=7.4 Hz), 2.00-2.15 (2H, m), 2.67 (2H, t, J=7.3 Hz), 2.75 (4H, brs), 3.21 (4H, brs), 3.40-3.50 (2H, m), 3.50-4.30 (2H, br), 4.13 (2H, t, J=6.5 Hz), 5.99 (1H, brs), 6.80 (1H, d, J=8.4 Hz), 6.90 (1H, d, J=7.6 Hz), 7.08 (1H, dd, J=2.1, 8.3 Hz), 7.19 (1H, d, J=2.1 Hz), 7.25-7.30 (1H, m), 7.35-7.45 (2H, m), 7.55 (1H, d, J=8.0 Hz).

Example 3095 Synthesis of 1-benzo[b]thiophen-4-yl-4-[3-(1-acetylpiperidin-4-yloxy)propyl]piperazine hydrochloride

Triethylamine (0.28 ml, 2.0 mmol) was added to a dichloromethane solution (15 ml) of 1-benzo[b]thiophen-4-yl-4-[3-(piperidin-4-yloxy)-propyl]-piperazine (0.45 g, 1.25 mmol) and the mixture was cooled in an ice bath. To this, acetyl chloride (0.1 ml, 1.4 mmol) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure. To the residue, 0.5 N hydrochloride-methanol solution (3 ml) was added. The crystal produced was obtained by filtration and dried to obtain 1-benzo[b]thiophen-4-yl-4-[3-(1-acetylpiperidin-4-yloxy)propyl]piperazine hydrochloride as white powder (0.36 g, 66% yield).

Melting point: 208-210° C.

Example 3096 Synthesis of 1-[3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]pyrrolidine-2,5-dione hydrochloride

PS-triphenylphosphine (3 mmol/g, 1.80 g), ditert-butylazodicarboxylate (1.27 g, 5.4 mmol) and N-hydroxysuccinimide (510 mg, 4.3 mmol) were added to a THF solution (50 ml) of 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propanol (1.00 g, 3.6 mmol) and the mixture was stirred at room temperature for 4 hours. The resin was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=1:2). The purified product was concentrated under reduced pressure to obtain white amorphous solid (762 mg, 47% yield). 157 mg of the white amorphous solid was dissolved in ethanol. To the solution, 1N hydrochloric acid-ethanol solution (0.42 ml) was added and further ether was added. The solution was stand still in a refrigerator. The crystal produced was filtrated and dried to obtain 1-[3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-pyrrolidine-2,5-dione hydrochloride 1158 mg) as a white powder.

Melting point: 255.0-257.0° C.

Example 3097 Synthesis of 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]naphthalene-1-carboxylic acid amide

Triethylamine (0.24 ml, 1.7 mmol) and isobutyl chloroformate (0.19 ml, 1.4 mmol) were added to an acetonitrile solution (10 ml) of 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-naphthalene-1-carboxylic acid (0.52 g, 1.2 mmol) under ice cooling and the mixture was stirred for 20 minutes. To the reaction solution, 28% ammonia water (0.5 ml) was added and the mixture was stirred at room temperature for 20 minutes. To the reaction solution, ethyl acetate was added and the solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-naphthalene-1-carboxylic acid amide (0.27 g, 53% yield) as white powder. Melting point 167.0-169.0° C.

Example 3098 Synthesis of 1-allyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-pyrazole-3-carboxylic acid methylamide

40% methylamine methanol solution (5 ml) was added to a methanol solution (5 ml) of 1-allyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 1.1 mmol) and the mixture was stirred at room temperature for 3 days. The solution was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 1-allyl-5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1H-pyrazole-3-carboxylic acid methylamide (0.32 g, 67% yield) as white powder.

Melting point 138.5-140.5° C.

Example 3099 Synthesis of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-cyclohexanecarboxylic acid amide

Ammonia water (28%, 0.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.36 g, 1.9 mmol) and 4-dimethylaminopyridine (DMAP) (0.05 g, 0.4 mmol) were added to a dichloromethane solution (10 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-cyclohexanecarboxylic acid (0.5 g, 1.2 mmol) and the mixture was stirred at room temperature for 19 hours. To the reaction solution, dichloromethane was added and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-cyclohexanecarboxylic acid amide (0.1 g, 22% yield), as white powder.

Melting point 107.5-108.5° C.

Example 3100 Synthesis of ethanesulfonic acid {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methyl-phenyl}amide hydrochloride

A dichloromethane solution (4 ml) of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenylamine (0.2 g, 0.49 mmol) was cooled on ice. To this, N-ethyldiisopropylamine (0.15 ml, 0.87 mmol) and ethane sulfonylchloride (0.07 ml, 0.73 mmol) were added and the mixture was stirred at room temperature for one hour. Further, N-ethyldiisopropylamine (0.15 ml, 0.87 mmol) and ethane sulfonylchloride (0.07 ml, 0.73 mmol) were added and the mixture was stirred at room temperature for 19 hours. To this, an aqueous 6N-sodium hydroxide solution (0.5 ml) and ethanol (2 ml) were added and the mixture was stirred at room temperature overnight. Dichloromethane was added to the reaction solution, which was then washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure. 4N-hydrochloride/ethyl acetate solution was added to the residue. The crystal generated was filtrated and dried to obtain ethanesulfonic acid {4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methyl-phenyl}amide hydrochloride (222 mg, 85% yield) as white powder.

Melting point: 235.5-237.5° C.

Example 3101 Synthesis of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}-carbamic acid methyl ester

A dichloromethane solution (2 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl-amine (0.17 g, 0.47 mmol) was cooled on ice. To this, pyridine (0.08 ml, 0.94 mmol) and methyl chloroformate (0.04 ml, 0.52 mmol) were added and the mixture was stirred at room temperature for 17 hours. To the reaction solution, ethyl acetate was added and the reaction mixture was washed with water. The water layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and thereafter, concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}carbamic acid methyl ester (0.10 g, 51% yield) as white powder.

Melting point: 162.5-165.0° C.

Example 3102 Synthesis of 3-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}-1,1-dimethyl-urea hydrochloride

A dichloromethane solution (5 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl-amine (0.27 g, 0.73 mmol) was cooled on ice. To this, triethylamine (0.36 ml, 2.5 mmol), dimethylcarbamoyl chloride (0.20 ml, 2.1 mmol) and pyridine (0.06 ml, 0.73 mmol) were added and the mixture was stirred at room temperature overnight. To the reaction solution, water was added and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1→0:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and a 4N-hydrochloride/ethyl acetate solution was added thereto. The crystal produced was filtrated and dried to obtain 3-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}-1,1-dimethyl-urea hydrochloride (0.10 g, 30% yield), as light yellow powder.

Melting point: 174.0-176.5° C.

Example 3103 Synthesis of 3-{5-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-1H-pyrazol-3-yl}-1,1-dimethyl-urea hydrochloride

An aqueous dimethylamine solution (50%, 0.16 ml, 1.6 mmol) was added to a DMF solution (3 ml) of 5-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-1H-pyrazol-3-yl carbamic acid phenyl ester (0.26 g, 0.52 mmol) and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=7:3→0:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. A 1N-hydrochloric acid/ethanol solution was added and the crystal produced was filtrated and dried to obtain 3-{5-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-1H-pyrazol-3-yl}-1,1-dimethyl-urea hydrochloride (95 mg, 37% yield) as white powder.

Melting point: 186.0-187.5° C.

Example 3104 Synthesis of N-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}-acetamide

Acetic anhydride (1 ml) and triethylamine (0.09 ml, 0.65 mmol) were added to a dichloromethane solution (4 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl-amine (0.20 g, 0.54 mmol) and the mixture was stirred at room temperature for 6 hours. An aqueous potassium carbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→0:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate-diisopropylether to obtain N-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}acetamide (0.19 g, 89% yield) as white powder.

Melting point: 137.0-139.0° C.

Example 3105 Synthesis of 3-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-hydroxymethyl-5-methoxy-phenyl}oxazolidin-2-one hydrochloride

First, 2-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-(2-oxo-oxazolidin-3-yl)benzaldehyde hydrochloride (1.28 g. 2.4 mmol)) was added to an aqueous potassium hydrochloride solution. The mixture was extracted with dichloromethane. The extracted solution was concentrated under reduced pressure and the residue was dissolved in THF (15 ml). To the solution, sodium borohydride (0.05 g, 1.2 mmol) was added under ice cooling and the mixture was stirred at room temperature for 3 hours. Then, 10% hydrochloric acid was added to the mixture under ice cooling to decompose the reagent excessively present. After an aqueous 6N sodium hydroxide solution was added to the solution to make it an alkaline solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=3:7→dichloromethane:methanol=100:3). The purified product was concentrated under reduced pressure and the residue was dissolved in ethanol. A 1N hydrochloric acid/ethanol solution was added to this. The crystal produced was recrystallized from ethanol to obtain 3-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-3-hydroxymethyl-5-methoxy-phenyl}oxazolidin-2-one hydrochloride (0.52 g, 41% yield) as white powder.

Melting point: 224.0-226.5° C. (decomposed)

Example 3106 Synthesis of 1-acetyl-4-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}piperazin hydrochloride

1-benzo[b]thiophen-4-yl-4-[3-(4-bromo-2-methoxy-6-methylphenoxy)propyl]piperazine hydrochloride (0.5 g, 0.98 mmol), 1-acetyl piperazine (0.15 g, 1.2 mmol), palladium acetate (11 mg, 0.048 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (BINAP)(63 mg, 0.098 mmol) and sodium t-butoxide (0.23 g, 2.3 mmol) were added to toluene (10 ml) and the mixture was stirred under an argon atmosphere at 90° C. for 22 hours. The reaction mixture was cooled to room temperature and filtrated by cerite. The filter cake was washed with ethyl acetate. The filtrate and wash liquid were combined and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=11:1→1:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. A 1N hydrochloric acid/ethanol solution was added to this and the crystal produced was filtrated and dried to obtain 1-acetyl-4-{4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-methoxy-5-methylphenyl}-piperazin hydrochloride (75 mg, 14% yield) as white powder.

Melting point: 257.0-261.0° C. (decomposed)

Example 3107 Synthesis of 1-benzo[b]thiophen-4-yl-4-[3-(4-imidazol-1-yl-2-methoxy-6-methyl-phenoxy)-propyl]-piperazine dihydrochloride

1-benzo[b]thiophen-4-yl-4-[3-(4-iodo-2-methoxy-6-methyl-phenoxy)-propyl]-piperazine (0.6 g, 0.69 mmol), imidazole (0.07 g, 1.03 mmol), copper iodide (I) (13 mg, 0.069 mmol), trans-N,N′-dimethyl-1,2-cyclohexanedimaine (0.02 ml, 0.14 mmol) and cesium carbonate (0.47 g, 1.38 mmol) were added to 1,4-dioxane (6 ml) and the mixture was refluxed with heating under an argon atmosphere for 50 hours. After the resultant reaction mixture was cooled to room temperature, water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=5:1→1:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. A 1N-hydrochloric acid/ethanol solution was added to this and the crystal produced was filtrated and dried to obtain 1-benzo[b]thiophen-4-yl-4-[3-(4-imidazol-1-yl-2-methoxy-6-methylphenoxy)propyl]-piperazine dihydrochloride (60 mg, 17% yield) as light yellow powder.

Melting point: 234.0-240.0° C. (decomposed).

Example 3108 Synthesis of 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,N-dimethyl-5-(2,2,2-trifluoroethoxy)benzamide hydrochloride

Cesium carbonate (0.34 g, 0.99 mmol) and 1,1,1-trifluoro-2-iodoethane (0.05 ml, 0.47 mmol) were added to a DMF solution (2 ml) of 4-[3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-hydroxy-5,N-dimethylbenzamide (188 mg, 0.39 mmol), and the mixture was stirred at 40° C. for 2 hours. Then, 1,1,1-trifluoro-2-iodoethane (0.1 ml, 0.94 mmol) was further added and the mixture was stirred at 40° C. for 5 hours. After the reaction mixture was cooled to room temperature, water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=3:1→0:1). The purified product was concentrated under reduced pressure and the residue was dissolved in isopropyl alcohol. A 1N-hydrochloric acid/ethanol solution was added to this and thereafter concentrated under reduced pressure. The residue was recrystallized from a solvent mixture of isopropyl alcohol/ethyl acetate to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,N-dimethyl-5-(2,2,2-trifluoro-ethoxy)benzamide hydrochloride (88 mg, 40% yield) as light yellow powder.

Melting point: 156.0-157.5° C.

Example 3109 Synthesis of 1-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}-ethanone hydrochloride

5-[3-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-1-methyl-1H-pyrazol-3-carboxylic acid methoxy methylamide hydrochloride (0.61 g, 1.3 mmol) was added to an aqueous sodium hydroxide solution and the solution mixture was extracted with dichloromethane. The extracted solution was concentrated under reduced pressure and the residue was dissolved in THF (12 ml). The solution was cooled to −78° C. and 1N-methyllithium ether solution (1.2 ml) was added thereto and the mixture was stirred at the same temperature for 2 hours. To the reaction solution, an aqueous ammonium chloride solution was added and the solution was heated to room temperature. Potassium chloride was added to the solution, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=3:1→0:1). The purified product was concentrated under reduced pressure and the residue was dissolved in ethanol. A 1N hydrochloric acid/ethanol solution was added to this and the crystal produced was recrystallized from water-containing ethanol to obtain 1-{5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazol-3-yl}ethanone hydrochloride (0.22 g, 40% yield) as white powder.

Melting point: 245.0° C. (decomposed)

Example 3110 Synthesis of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-hydroxymethyl-1-methyl-1H pyrazole

A THF solution (8 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-(tert-butyl-dimethylsilanyloxymethyl)-1-methyl-1H-pyrazole (0.75 g, 1.5 mmol) was cooled on ice and a 1M THF solution of tetrabutyl ammonium fluoride (1.7 ml) was added thereto. The mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→30:1→15:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate and diisopropyl ether to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-3-hydroxymethyl-1-methyl-1H-pyrazole (0.46 g, 79% yield) as white powder.

Melting temperature: 123.5-126.0° C.

Pharmacological Test 1

1) Dopamine D₂ Receptor Binding Assay

The assay was performed according to the method by Kohler et al. (Kohler C, Hall H, Ogren S O and Gawell L, Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain. Biochem. Pharmacol., 1985; 34: 2251-2259).

Wistar male rats were decapitated, the brain was retrieved immediately and corpus striatum was taken out. It was homogenized in 50 mM tris(hydroxymethyl)aminomethane (Tris)-hydrochloric acid buffer (pH 7.4) of a volume 50 times of the weight of the tissue using a homogenizer with a high-speed rotating blade, and centrifuged at 4° C., 48,000×g for 10 minutes. The obtained precipitate was suspended again in the above-described buffer of a volume 50 times of the weight of the tissue and after incubated at 37° C. for 10 minutes, centrifuged in the above-described condition. The obtained precipitate was suspended in 50 mM (Tris)-hydrochloric acid buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, pH 7.4) of a volume 25 times of the weight of the tissue and preserved by freezing at −85° C. till it was used for binding assay as a membrane specimen.

The binding assay was performed using 40 μl of the membrane specimen, 20 μl of [³H]-raclopride (final concentration 1 to 2 nM), 20 μl of a test drug and 50 mM Tris-hydrochloric acid buffer (containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, pH 7.4) so that the total amount was 200 μl (final dimethylsulfoxide concentration 1%). The reaction was performed at room temperature for 1 hour and terminated by conducting suction filtration with a cell harvester on a glass fiber filter plate. The filter plate made of glass fiber was washed with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and after dried, a microplate liquid scintillation cocktail was added and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 μM (+)-butaclamol hydrochloride was assumed as nonspecific binding.

IC₅₀ value was calculated from concentration-dependent reaction using a non-linear analysis program. Ki value was calculated from IC₅₀ value using Cheng-Prussoff formula. The results are shown in the following Table 312.

TABLE 312 Dopamine D2 receptor binding test Test compound Ki (nM) Compound of Example 3 1.5 Compound of Example 4 1.9 Compound of Example 6 0.7 Compound of Example 7 0.8 Compound of Example 11 0.2 Compound of Example 14 0.3 Compound of Example 15 0.4 Compound of Example 17 0.6 Compound of Example 26 2.6 Compound of Example 27 1.5 Compound of Example 32 2.5 Compound of Example 40 3.1 Compound of Example 48 2.3 Compound of Example 58 2.0 Compound of Example 61 5.0 Compound of Example 62 1.6 Compound of Example 72 3.4 Compound of Example 73 1.3 Compound of Example 76 2.5 Compound of Example 80 1.6 Compound of Example 94 2.4 Compound of Example 95 1.9 Compound of Example 112 1.0 Compound of Example 115 1.6 Compound of Example 121 1.1 Compound of Example 123 0.7 Compound of Example 125 2.0 Compound of Example 127 0.4 Compound of Example 133 0.3 Compound of Example 144 0.4 Compound of Example 146 0.1 Compound of Example 160 0.4 Compound of Example 169 0.9 Compound of Example 170 1.0 Compound of Example 186 1.3 Compound of Example 190 1.2 Compound of Example 232 1.1 Compound of Example 241 0.4 Compound of Example 243 0.2 Compound of Example 252 0.3 Compound of Example 271 1.2 Compound of Example 281 0.3 Compound of Example 286 0.2 Compound of Example 301 0.2 Compound of Example 303 1.0 Compound of Example 307 0.3 Compound of Example 313 0.7 Compound of Example 314 0.8 Compound of Example 323 1.5 Compound of Example 340 1.9 Compound of Example 343 0.9 Compound of Example 345 1.6 Compound of Example 354 0.2 Compound of Example 358 0.2 Compound of Example 359 0.2 Compound of Example 363 2.0 Compound of Example 368 0.4 Compound of Example 382 0.5 Compound of Example 394 3.8 Compound of Example 453 0.9 Compound of Example 462 0.4 Compound of Example 546 0.6 Compound of Example 650 1.2 Compound of Example 706 1.0 Compound of Example 802 0.6 Compound of Example 1014 3.3 Compound of Example 1016 2.2 Compound of Example 1026 1.9 Compound of Example 1027 1.9 Compound of Example 1034 2.1 Compound of Example 1059 0.4 Compound of Example 1060 0.1 Compound of Example 1061 0.1 Compound of Example 1071 0.1 Compound of Example 1076 1.2 Compound of Example 1079 0.4 Compound of Example 1080 0.6 Compound of Example 1083 0.3 Compound of Example 1084 0.1 Compound of Example 1086 1.0 Compound of Example 1087 0.3 Compound of Example 1089 1.0 Compound of Example 1106 1.0 Compound of Example 1110 1.2 Compound of Example 1113 0.7 Compound of Example 1138 1.4 2) Serotonin 5-HT_(2A) Receptor Binding Assay

The assay was performed according to the method by Leysen J E et al. (Leysen J E, Niemegeers C J E, Van Nueten J M and Laduron P M. [3H] Ketanserin (R 41 468), a selective 3H-ligand for serotonin 2 receptor binding sites. Mol. Pharmacol., 1982, 21: 301-314).

Wistar male rats were decapitated, the brain was retrieved immediately and frontal cortex was taken out. It was homogenized in 0.25 M sucrose of a volume 10 times of the weight of the tissue using a Teflon glass homogenizer, and centrifuged at 4° C., 1,000×g for 10 minutes. The obtained supernatant was transferred to another centrifuge tube and suspended in 0.25 M sucrose of a volume 5 times of the weight of the tissue and the precipitate was centrifuged in the above-described condition. The obtained supernatant was combined with the supernatant obtained above and adjusted to a volume 40 times of the weight of the tissue with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and centrifuged at 4° C., 35,000×g for 10 minutes. The obtained precipitate was suspended again in the above-described buffer of a volume 40 times of the weight of the tissue and centrifuged in the above-described condition. The obtained precipitate was suspended in the above-described buffer of a volume 20 times of the weight of the tissue and preserved by freezing at −85° C. till it was used for binding assay as a membrane specimen.

The binding assay was performed using 40 μl of the membrane specimen, 20 μl of [³H]-Ketanserin (final concentration 1 to 3 nM), 20 μl of a test drug and 50 mM Tris-hydrochloric acid buffer (pH 7.4) so that the total amount was 200 μl (final dimethylsulfoxide concentration 1%). The reaction was performed at 37° C. for 20 minutes and terminated by conducting suction filtration with a cell harvester on a glass fiber filter plate.

The filter plate made of glass fiber was washed with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and after dried, a microplate liquid scintillation cocktail was added and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 μM spiperone was assumed as nonspecific binding.

IC₅₀ value was calculated from concentration-dependent reaction using a non-linear analysis program. Ki value was calculated from IC₅₀ value using Cheng-Prussoff formula. The results are shown in the following Table 313

TABLE 313 Serotonion 5-HT_(2A) receptor binding test Test compound Ki (nM) Compound of Example 3 6.0 Compound of Example 4 7.7 Compound of Example 6 3.3 Compound of Example 7 2.9 Compound of Example 11 4.4 Compound of Example 14 2.4 Compound of Example 15 5.9 Compound of Example 17 3.4 Compound of Example 26 0.8 Compound of Example 27 1.0 Compound of Example 32 1.4 Compound of Example 40 0.6 Compound of Example 48 3.8 Compound of Example 58 4.9 Compound of Example 61 4.9 Compound of Example 62 4.7 Compound of Example 72 3.4 Compound of Example 73 5.6 Compound of Example 76 1.7 Compound of Example 80 3.3 Compound of Example 94 2.0 Compound of Example 95 2.3 Compound of Example 112 0.7 Compound of Example 115 3.7 Compound of Example 121 1.5 Compound of Example 123 1.4 Compound of Example 125 3.9 Compound of Example 127 2.4 Compound of Example 133 4.7 Compound of Example 144 1.4 Compound of Example 146 2.4 Compound of Example 160 0.6 Compound of Example 169 2.6 Compound of Example 170 3.3 Compound of Example 186 2.0 Compound of Example 190 0.6 Compound of Example 232 2.7 Compound of Example 241 0.7 Compound of Example 243 0.5 Compound of Example 252 0.3 Compound of Example 271 0.6 Compound of Example 281 0.6 Compound of Example 286 0.8 Compound of Example 301 0.4 Compound of Example 303 2.5 Compound of Example 307 0.7 Compound of Example 313 1.1 Compound of Example 314 0.8 Compound of Example 323 0.7 Compound of Example 340 4.8 Compound of Example 343 0.5 Compound of Example 345 1.9 Compound of Example 354 0.6 Compound of Example 358 1.1 Compound of Example 359 1.1 Compound of Example 363 1.1 Compound of Example 368 0.7 Compound of Example 382 0.6 Compound of Example 394 4.7 Compound of Example 453 1.2 Compound of Example 462 1.7 Compound of Example 546 0.7 Compound of Example 650 0.6 Compound of Example 706 0.9 Compound of Example 802 1.4 Compound of Example 1014 4.2 Compound of Example 1016 2.3 Compound of Example 1026 3.5 Compound of Example 1027 2.0 Compound of Example 1034 3.1 Compound of Example 1059 3.8 Compound of Example 1060 1.2 Compound of Example 1061 1.2 Compound of Example 1071 1.3 Compound of Example 1076 12.4 Compound of Example 1079 2.8 Compound of Example 1080 3.4 Compound of Example 1083 1.5 Compound of Example 1084 1.4 Compound of Example 1086 5.8 Compound of Example 1087 2.6 Compound of Example 1089 13.9 Compound of Example 1106 7.1 Compound of Example 1110 4.9 Compound of Example 1113 5.0 Compound of Example 1138 19.7 3) Adrenalin α1 Receptor Binding Assay

The assay was performed according to the method by Groβ G et al. (Groβ G, Hanft G and Kolassa N. Urapidil and some analogues with hypotensive properties show high affinities for 5-hydroxytryptamine (5-HT) binding sites of the 5-HT1A subtype and for α1-adrenoceptor binding sites. Naunyn-Schmiedeberg's Arch Pharmacol., 1987, 336: 597-601).

Wistar male rats were decapitated, the brain was retrieved immediately and cerebral cortex was taken out. It was homogenized in 50 mM Tris-hydrochloric acid buffer (100 mM NaCl, containing 2 mM dihydrogen disodium ethylene diamine tetraacetate, pH 7.4) of a volume 20 times of the weight of the tissue using a homogenizer with a high-speed rotating blade, and centrifuged at 4° C., 80,000×g for 20 minutes. The obtained precipitate was suspended in the above-described buffer of a volume 20 times of the weight of the tissue and after incubated at 37° C. for 10 minutes, centrifuged in the above-described condition. The obtained precipitate was suspended again in the above-described buffer of a volume 20 times of the weight of the tissue and centrifuged in the above-described condition. The obtained precipitate was suspended in 50 mM (Tris)-hydrochloric acid buffer (containing 1 mM dihydrogen disodium ethylene diamine tetraacetate, pH 7.4) of a volume 20 times of the weight of the tissue and preserved by freezing at −85° C. till it was used for binding assay as a membrane specimen.

The binding assay was performed using 40 μl of the membrane specimen, 20 μl of [³H]-prazosin (final concentration 0.2 to 0.5 nM), 20 μl of a test drug and 50 mM Tris-hydrochloric acid buffer (containing 1 mM EDTA, pH 7.4) so that the total amount was 200 μl (final dimethylsulfoxide concentration 1%). The reaction was performed at 30° C. for 45 minutes and terminated by conducting suction filtration with a cell harvester on a glass fiber filter plate.

The filter plate made of glass fiber was washed with 50 mM Tris-hydrochloric acid buffer (pH 7.4), and after dried, a microplate liquid scintillation cocktail was added and the radioactivity was measured with a microplate scintillation counter. Radioactivity in the presence of 10 μM phentolamine hydrochloride was assumed as nonspecific binding.

IC₅₀ value was calculated from concentration-dependent reaction using a non-linear analysis program. Ki value was calculated from IC₅₀ value using Cheng-Prussoff formula.

Pharmacological Test 2

Partial Agonistic Activity on Dopamine D₂ Receptor Using D₂ Receptor Expression Cells

Partial agonistic activity on dopamine D₂ receptor was evaluated by quantitatively determining cyclic AMP production inhibitory effect of a test compound in dopamine D₂ receptor expression cells in which adenosine 3′,5′-cyclic monophosphate (cyclic AMP) production was induced by forskolin stimulation.

Human recombinant dopamine D₂ receptor expressing Chinese hamster ovary/DHFR(−) cells were cultured in a culture medium (Iscove's Modified Dulbecco's Medium (IMDM culture medium), 10% fetal bovine serum, 50 I.U./ml penicillin, 50 μg/ml streptomycin, 200 μg/ml geneticin, 0.1 mM sodium hypoxanthine, 16 μM thymidine) at 37° C. and 5% carbon dioxide condition. Cells were seeded at 10⁴ cells/well on a 96-well microtiter plate coated with poly-L-lysine and grown under the same condition for 2 days. Each well was washed with 100 μl of a culture medium (IMDM culture medium, 0.1 mM sodium hypoxanthine, 16 μM thymidine). The culture medium was replaced with 50 μl of culture medium (IMDM culture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μM thymidine) having dissolved therein 3 μM of a test compound. After allowed to incubate at 37° C., 5% carbon dioxide condition for 20 minutes, the culture medium was replaced with 100 μl of forskolin stimulative culture medium (IMDM culture medium, 0.1% sodium ascorbate, 0.1 mM sodium hypoxanthine, 16 μM thymidine, 10 μM forskolin, 500 μM 3-isobutyl-1-methylxanthine) having 3 μM of the test compound dissolved therein and allowed to incubate at 37° C., 5% carbon dioxide condition for 10 minutes. After the culture medium was removed, 200 μl of Lysis 1B aqueous solution (Amersham Bioscience, reagent attached to cyclic AMP biotrack enzyme immunoassay system) was dispensed and shaken for 10 minutes. The aqueous solution of each well was used as a sample for measurement. Samples for measurement quadruply diluted were subjected to measurement of the quantity of cyclic AMP using the above-described enzyme immunoassay system. Inhibition ratio of the respective test compound was calculated assuming that the quantity of cyclic AMP of the well to which no test compound was added was 100%. In this empiric test system, dopamine which was used as a control drug suppressed the quantity of cyclic AMP to about 10% as the maximum activity.

It was confirmed that test compounds had partial agonistic activity for dopamine D₂ receptor in the above-described test.

Since the test compounds has partial agonistic activity for dopamine D₂ receptor, they can stabilize dopamine neurotransmission to a normal condition in a schizophrenia patient and as a result, exhibit, for example, positive and negative condition improving effect, cognitive impairment improving effect and the other symptom improving effects without causing side effects.

Pharmacological Test 3

Inhibitory Effect on Apomorphine-Induced Stereotyped Behavior in Rats

Wistar rats (male, six-seven weeks old, Japan SLC, Inc.) were used as test animals. A test compound was suspended in 5% gum arabic/(physiological saline or water) using an agate mortar and was diluted with the same solvent if necessary.

Test animals were fasted overnight from the day before. Apomorphine (0.7 mg/kg) was subcutaneously administered (1 ml/kg) 1 hour after each test compound was orally administered (5 ml/kg). Stereotyped behavior was observed for 1 minute respectively 20, 30 and 40 minutes after apomorphine injection.

The stereotyped behavior of each animal was quantified according to the following condition and score made at three points were summed up and the anti-apomorphine effect was evaluated. Six test animals were used for each group.

0: The appearance of the animals is the same as saline treated rats;

1: Discontinuous sniffing, constant exploratory activity;

2: Continuous sniffing, periodic exploratory activity;

3: Continuous sniffing, discontinuous biting, gnawing or licking. Very brief periods of locomotor activity;

4: Continuous biting, gnawing or licking; no exploratory activity.

Non-clinical statistical analysis system was used for all statistical processing. When the significance probability value was lower than 0.05, it was judged that a significant difference existed. The difference of the score between the solvent administration group and each test compound administration group was analyzed using Wilcoxon rank-sum test or Steel test. In addition, linear regression analysis was used for calculating 50% effective dose (95% confidence interval).

Since the test compounds showed inhibitory effect for apomorphine-induced stereotyped behavior, it was confirmed that the test compounds have D₂ receptor antagonistic effect.

Pharmacological Test 4

Inhibitory Effect on (±)D-2,5-dimethoxy-4-iodoamphetamine (DOI) Induced Head Twitch in Rats

Wistar rats (male, six-seven weeks old, Japan SLC, Inc.) were used as test animals. A test compound was suspended in 5% gum arabic/(physiological saline or water) using an agate mortar and was diluted with the same solvent if necessary.

Test animals were fasted overnight from the day before. DOI (5.0 mg/kg) was subcutaneously administered (1 ml/kg) 1 hour after each test compound was orally administered (5 ml/kg). The number of head twitches was counted for 10 minutes immediately after DOI injection. Six test animals were used for each group.

Non-clinical statistical analysis was used for all statistical processing. When the significance probability value was lower than 0.05, it was judged that a significant difference existed. The difference of the number of head twitches between the solvent administration group and each test compound administration group was analyzed using t-test or Dunnett's test. In addition, linear regression analysis was used for calculating 50% effective dose (95% confidence interval).

Since the test compounds showed inhibitory effect for DOI-induced head twitch, it was confirmed that the test compounds have serotonin 5HT_(2A) receptor antagonistic effect.

Pharmacological Test 5

Catalepsy Inducing Effect in Rats

Wistar rats (male, six-seven weeks old, Japan SLC, Inc.) were used as test animals. A test compound was suspended in 5% gum arabic/(physiological saline or water) using an agate mortar and was diluted with the same solvent if necessary.

Test animals were fasted overnight from the day before observation on catalepsy and ptosis was performed 1, 2, 4, 6 and 8 hours after each test compound was orally administered (5 ml/kg). Six test animals were used for each group.

One forepaw of a rat was placed on an edge of a steel small box (width: 6.5 cm, depth: 4.0 cm, height: 7.2 cm) (an unnatural pose) and when the rat maintained the pose for more than 30 seconds, it was judged that the case was catalepsy positive. This observation was performed three times at each point, and if there was at least one positive case, it was judged that catalepsy occurred in the individual.

As a result, catalepsy induction effect of a test compound was dissociated from inhibitory effect on apomorphine-induced stereotyped behavior, therefore it was suggested that apprehension for extrapyramidal side effect in clinic would be low.

Pharmacological Test 6

Measurement of Serotonin (5-HT) Uptake Inhibitory Activity of a Test Compound by Rat Brain Synaptosome

Wistar male rats were decapitated, the brain was retrieved and frontal cortex was dissected out, and it was homogenized in 0.32 M sucrose solution of a weight 20 times of the weight of the tissue using a Potter type homogenizer. The homogenate was centrifuged at 4° C., 1,000×g for 10 minutes, the obtained supernatant was further centrifuged at 4° C., 20,000×g for 20 minutes, and the pellet was suspended in an incubation buffer (20 mM Hepes buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, 1.5 mM calcium chloride), which was used as crude synaptosome fraction.

5-HT uptake reaction was performed in a volume of 200 μl using a 96-well round bottom plate and pargyline (final concentration 10 μM) and sodium ascorbate (final concentration 0.2 mg/ml) were contained in the incubation buffer upon reaction and used.

Incubation buffer (total counting), non-labeled 5-HT (final concentration 10 μM, non-specific counting) and the diluted test compound (final concentration 300 nM) were added to each well. One-tenth quantity of the final volume of the synaptosome fraction was added and after preincubated at 37° C. for 10 minutes, tritium labeled 5-HT solution (final concentration 8 nM) was added and uptake reaction was started at 37° C. The uptake time was 10 minutes and the reaction was terminated by vacuum filtration through a 96-well fiber glass filter paper plate, and after the filter paper was washed with cold normal saline, it was dried enough and Microscint0 (Perkin-Elmer) was added to the filter and remaining radioactivity on the filter was measured.

Serotonin uptake inhibitory activity (%) was calculated from the radioactivity of total counting as 100%, of non-specific counting as 0%, and of counting obtained with test compound. % of inhibition of 5-HT(%)=100−[(Count obtained with test compound−Nonspecific count(0% Uptake))/(Total count(100% Uptake)−Nonspecific count(0% Uptake))]×100 The results are shown in the next Table 314.

TABLE 314 Serotonin uptake inhibitory Test compound ratio (%) (300 nM) Compound of Example 11 95.2 Compound of Example 15 95.3 Compound of Example 802 96.6 Compound of Example 1071 94.4 Compound of Example 1076 87.8 Compound of Example 1089 85.0 Compound of Example 1083 96.3 Compound of Example 1106 69.9 Compound of Example 1079 82.3 Compound of Example 1080 95.6 Compound of Example 1138 67.2 Compound of Example 1059 97.2 Compound of Example 1060 97.5 Compound of Example 1061 97.5 Compound of Example 1110 38.5 Compound of Example 1086 98.6 Compound of Example 1087 97.1 Compound of Example 1113 59.3

Preparation Examples

100 g of a compound of the present invention, 40 g of Avicel (trade name, product of Asahi Chemical Industry Co., Ltd.), 30 g of corn starch and 2 g of magnesium stearate was mixed and polished and tableted with a pestle for glycocalyx R10 mm.

The obtained tablet was coated with a film using a film coating agent made up of 10 g of TC-5 (trade name, product of Shin-Etsu Chemical Co., Ltd., hydroxypropyl methylcellulose), 3 g of polyethylene glycol 6000, 40 g of castor oil and an appropriate amount of ethanol to produce a film coated tablet of the above composition. 

The invention claimed is:
 1. A heterocyclic compound or a salt thereof represented by formula (1):

where R² represents a hydrogen atom or a lower alkyl group; A represents a lower alkylene group or a lower alkenylene group; and R¹ represents a heterocyclic group selected from the group consisting of a pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, isoxazolyl group, thiazolyl group, and thienyl group; wherein at least one group selected from the group consisting of the groups (1) to (66) below may be present as a substituent on the heterocyclic group represented by R¹: (1) a lower alkyl group, (2) a lower alkenyl group, (3) a halogen substituted lower alkyl group, (4) a lower alkoxy group, (5) an aryloxy group, (6) a lower alkylthio group, (7) a halogen substituted lower alkoxy group, (8) a hydroxy group, (9) a protected hydroxy group, (10) a hydroxy lower alkyl group, (11) a protected hydroxy lower alkyl group, (12) a halogen atom, (13) a cyano group, (14) an aryl group, (15) a nitro group, (16) an amino group, (17) an amino group having a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group, and a lower alkoxy carbonylamino lower alkanoyl group as a substituent, (18) a lower alkanoyl group, (19) an arylsulfonyl group that may have a lower alkyl group(s) on the aryl group, (20) a carboxy group, (21) a lower alkoxycarbonyl group, (22) a carboxy lower alkyl group, (23) a lower alkoxycarbonyl lower alkyl group, (24) a lower alkanoylamino lower alkanoyl group, (25) a carboxy lower alkenyl group, (26) a lower alkoxycarbonyl lower alkenyl group, (27) a carbamoyl lower alkenyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group as a substituent, (28) a carbamoyl group that may have a group(s) selected from the group consisting of the groups (i) to (lxxviii) below as a substituent: (i) a lower alkyl group, (ii) a lower alkoxy group, (iii) a hydroxy lower alkyl group, (iv) a lower alkoxy lower alkyl group, (v) an aryloxy lower alkyl group, (vi) a halogen substituted lower alkyl group, (vii) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an aroyl group, and a carbamoyl group, (viii) a cyclo C3-C8 alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group, and a phenyl lower alkoxy group as a substituent, (ix) a cyclo C3-C8 alkyl substituted lower alkyl group, (x) a lower alkenyl group, (xi) a carbamoyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, phenyl group that may have a lower alkyl group(s), and a phenyl group(s) that may have a lower alkoxy group(s) as a substituent, (xii) a lower alkoxycarbonyl lower alkyl group, (xiii) a furyl lower alkyl group (that may have a lower alkyl group(s) as a substituent) on the furyl group, (xiv) a tetrahydrofuryl lower alkyl group, (xv) a 1,3-dioxolanyl lower alkyl group, (xvi) a tetrahydropyranyl lower alkyl group, (xvii) a pyrrolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrrolyl group), (xviii) a lower alkyl group substituted with a dihydropyrazolyl group that may have an oxo group(s), (xix) a pyrazolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazolyl group), (xx) an imidazolyl lower alkyl group, (xxi) a pyridyl lower alkyl group, (xxii) a pyrazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazinyl group), (xxiii) a pyrrolidinyl lower alkyl group (that may have a group(s) selected from the group consisting of an oxo group(s) and a lower alkyl group as a substituent on the pyrrolidinyl group), (xxiv) a piperidyl lower alkyl group (that may have a group(s) selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent on the piperidyl group), (xxv) a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group), (xxvi) a morpholinyl lower alkyl group, (xxvii) a thienyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the thienyl group), (xxviii) a thiazolyl lower alkyl group, (xxix) a dihydrobenzofuryl lower alkyl group, (xxx) a benzopyranyl lower alkyl group (that may have an oxo group(s) as a substituent on the benzopyranyl group), (xxxi) a benzimidazoyl lower alkyl group, (xxxii) an indolyl lower alkyl group that may have a lower alkoxycarbonyl group(s) on the lower alkyl group, (xxxiii) an imidazolyl lower alkyl group that has a substituent(s) selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group on the lower alkyl group, (xxxiv) a pyridyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio lower alkyl group as a substituent, (xxxv) a pyrrolidinyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and an aroyl group as a substituent, (xxxvi) a piperidyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and an aroyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen atom as a substituent, (xxxvii) a tetrahydrofuryl group that may have an oxo group(s), (xxxviii) a hexahydroazepinyl group that may have an oxo group(s), (xxxix) a pyrazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, an aryl group, and a furyl group as a substituent, (xl) a thiazolyl group, (xli) a thiadiazolyl group that may have a lower alkyl group(s), (ilii) an isoxazolyl group that may have a lower alkyl group(s), (xliii) an indazolyl group, (xliv) an indolyl group, (xlv) a tetrahydrobenzothiazolyl group, (xlvi) a tetrahydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and an oxo group as a substituent, (xlvii) a quinolyl group that may have a lower alkyl group(s), (xlviii) a benzodioxolyl lower alkyl group, (xlix) an aryl group that may have a group(s) as a substituent, selected from the group consisting of a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group, and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; an aryloxy group; an aryl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an aryl group; a pyrazolyl group; a pyrrolidinyl group that may have an oxo group(s); an oxazolyl group; an imidazolyl group that may have a lower alkyl group(s); a dihydrofuryl group that may have an oxo group(s); a thiazolidinyl lower alkyl group that may have an oxo group(s); an imidazolyl lower alkanoyl group; and a piperidinylcarbonyl group, (l) a cyano lower alkyl group, (li) a dihydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an oxo group, (lii) a halogen substituted lower alkylamino group, (liii) a lower alkylthio lower alkyl group, (liv) an amidino group that may have a lower alkyl group(s), (lv) an amidino lower alkyl group, (lvi) a lower alkenyloxy lower alkyl group, (lvii) an arylamino group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, and a halogen substituted lower alkoxy group, on the aryl group, (lviii) an aryl lower alkenyl group, (lix) a pyridylamino group that may have a lower alkyl group(s), (lx) an aryl lower alkyl group (that may have on the aryl group and/or the lower alkyl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, a carbamoyl group, and a lower alkoxycarbonyl group as a substituent), (lxi) a lower alkynyl group, (lxii) an aryloxy lower alkyl group (that may have as a substituent on the aryl group a group(s) selected from the group consisting of a lower alkoxy group, a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkoxy group and a lower alkyl group, and a pyrrolidinyl group that may have an oxo group(s)), (lxiii) an isoxazolidinyl group that may have an oxo group(s), (lxiv) a dihydroindenyl group, (lxv) an aryl lower alkoxy lower alkyl group, (lxvi) a tetrahydropyranyl group, (lxvii) an azetidinyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and an aroyl group, (lxviii) an azetidinyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and aroyl group, (lxix) a tetrazolyl group, (lxx) an indolinyl group that may have an oxo group(s), (lxxi) a triazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a lower alkylthio group, (lxxii) an imidazolyl group that may have a carbamoyl group(s), (lxxiii) an oxazolyl group that may have a lower alkyl group(s), (lxxiv) an isothiazolyl group that may have a lower alkyl group(s), (lxxv) a benzimidazolyl group, (lxxvi) a dihydrobenzothiazolyl group that may have an oxo group(s), (lxxvii) a thienyl group that may have a lower alkoxycarbonyl group(s), and (lxxviii) an oxazolyl lower alkyl group that may have a lower alkyl group(s), (29) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, an aryl group, an aryl lower alkyl group, an aroyl group, and an amino substituted alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group) on the amino group, (30) a lower alkyl group substituted with a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group, (31) a thiocarbamoyl group that may have a lower alkyl group(s), (32) a sulfamoyl group, (33) an oxazolidinyl group that may have an oxo group(s), (34) an imidazolidinyl group that may have a substituent(s) selected from the group consisting of an oxo group and a lower alkyl group, (35) a pyrrolidinyl group that may have an oxo group(s), (36) an imidazolyl group, (37) a triazolyl group, (38) an isoxazolyl group, (39) a piperidyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an arylsulfonyl group, an oxo group, a hydroxy group, and an amino group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and lower alkanoylamino lower alkanoyl group, (40) a piperidylcarbonyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and an aroyl group may be present), a piperidyl group (on which a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group, and an aroyl group may be present), a piperazinyl group (on which a lower alkyl group(s) may be present as a substituent), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepinyl group (on which a lower alkyl group(s) may be present as a substituent), a pyridyl group, a pyridyloxy group, a pyridyl lower alkoxy group, a tetrahydroquinolyl group (on which an oxo group(s) may be present), a benzodioxolyl group, an aryl lower alkoxy group (that may have a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkoxy group on the aryl group), an aryl group (on which a group(s) selected from the group consisting of a halogen atom, a lower alkoxy group, and a hydroxy group may be present), an aryloxy group (that may have on the aryl group a group(s) selected from the group consisting of a cyano group, a halogen atom, lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), an aryl lower alkyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), and an aroyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom and a lower alkoxy group), (41) a pyrrolidinylcarbonyl group that may have a group as a substituent, selected from the group consisting of a hydroxy lower alkyl group, a carbamoyl group, a hydroxy group, an amino group (that may have on the amino group a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, and an aroyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group), an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), an aryloxy group (that may have a halogen substituted lower alkoxy group(s) on the aryl group), an aryloxy lower alkyl group (that may have a halogen substituted lower alkoxy group(s) on the aryl group), and a tetrahydroquinolyl group (on which an oxo group(s) may be present), (42) a piperazinylcarbonyl group that may have a group(s) as a substituent, selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), a piperidyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxolanyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have a phenyl group(s) as a substituent on the lower alkyl group), a imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group (that may have a lower alkyl group(s) as a substituent), pyridyl group (that may have on the pyridyl group a group(s) selected from the group consisting of a lower alkyl group, a cyano group, and a halogen substituted lower alkyl group as a substituent), a thieno[2,3-b]pyridyl group, an aryl group (on which a group(s) selected from the group consisting of a halogen atom and a lower alkyl group may be present), an aroyl group, a furyl carbonyl group, an aryl lower alkoxycarbonyl group, and an oxo group, (43) a hexahydroazepinylcarbonyl group, (44) a hexahydro-1,4-diazepinylcarbonyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and a pyridyl group, (45) a dihydropyrrolylcarbonyl group that may have a lower alkyl group(s), (46) a thiomorpholinylcarbonyl group, (47) a morpholinylcarbonyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group, and an aryl group, (48) a thiazolidinyl carbonyl group that may have an aryl group(s) that may have a group(s) selected from the group consisting of a lower alkoxy group and a cyano group, (49) an azabicyclo[3.2.2]nonylcarbonyl group, (50) an 8-azabicyclo[3.2.1]octylcarbonyl group that may have a halogen substituted or unsubstituted aryloxy group(s), (51) an indolinylcarbonyl group, (52) a tetrahydroquinolylcarbonyl group, (53) a tetrahydropyrido[3.4-b]indolylcarbonyl group, (54) a morpholinyl lower alkyl group, (55) a piperazinyl lower alkyl group that may have a lower alkyl groups) on the piperazinyl group, (56) a morpholinylcarbonyl lower alkyl group, (57) a piperazinylcarbonyl lower alkyl group that may have a lower alkyl group(s) on the piperazinyl group, (58) an oxo group, (59) an amino lower alkoxy group (that may have a lower alkyl group(s) on the amino group), (60) a lower alkoxy lower alkoxy group, (61) a piperazinyl group that may have a group(s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group, and a lower alkoxycarbonyl group, (62) a morpholinyl group, (63) a 1,3,8-triazaspiro[4,5]decanylcarbonyl group that may have a group(s) selected from the group consisting of an oxo group and an aryl group, (64) a tetrahydropyridylcarbonyl group that may have a pyridyl group(s), (65) an imidazolidinylcarbonyl group that may have a thioxo group(s), and (66) a 1,4-dioxa-8-azaspiro[4.5]decanyl group.
 2. The compound according to claim 1, wherein R¹ represents a heterocyclic group selected from the group consisting of a pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, isoxazolyl group, thiazolyl group, and thienyl group; and wherein from 1 to 5 groups selected from the group consisting of the groups (1) to (66) below may be present as a substituent(s) on the heterocyclic group represented by R¹; (1) a lower alkyl group, (2) a lower alkenyl group, (3) a halogen substituted lower alkyl group, (4) a lower alkoxy group, (5) a phenoxy group, (6) a lower alkylthio group, (7) a halogen substituted lower alkoxy group, (8) a hydroxy group, (9) a phenyl lower alkoxy group, (10) a hydroxy lower alkyl group, (11) a lower alkoxy lower alkyl group, (12) a halogen atom, (13) a cyano group, (14) a phenyl group, (15) a nitro group, (16) an amino group, (17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group, and a lower alkoxycarbonylamino lower alkanoyl group as a substituent(s), (18) a lower alkanoyl group, (19) a phenylsulfonyl group that may have a single lower alkyl group on the phenyl group, (20) a carboxy group, (21) a lower alkoxycarbonyl group, (22) a carboxy lower alkyl group, (23) a lower alkoxycarbonyl lower alkyl group, (24) a lower alkanoylamino lower alkanoyl group, (25) a carboxy lower alkenyl group, (26) a lower alkoxycarbonyl lower alkenyl group, (27) a carbamoyl lower alkenyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a lower alkyl group substituted with 1 to 3 halogen atoms as a substituent(s), (28) a carbamoyl group that may have 1 to 2 groups selected from the group consisting of the groups (i) to (lxxviii) below as a substituent(s): (i) a lower alkyl group, (ii) a lower alkoxy group, (iii) a hydroxy lower alkyl group, (iv) a lower alkoxy lower alkyl group, (v) an phenoxy lower alkyl group, (vi) a halogen substituted lower alkyl group, (vii) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a carbamoyl group, (viii) a cyclo C3-C8 alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group, and a phenyl lower alkoxy group as a substituent(s), (ix) a cyclo C3-C8 alkyl substituted lower alkyl group, (x) a lower alkenyl group, (xi) a lower alkyl group having 1 to 2 carbamoyl groups that may have 1 to 2 groups as a substituent(s) selected from the group consisting of a lower alkyl group, a phenyl group that may have a single lower alkyl group, and a phenyl group that may have a single lower alkoxy group, (xii) a lower alkyl group having 1 to 2 lower alkoxy carbonyl groups, (xiii) a furyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the furyl group), (xiv) a tetrahydrofuryl lower alkyl group, (xv) a 1,3-dioxolanyl lower alkyl group, (xvi) a tetrahydropyranyl lower alkyl group, (xvii) a pyrrolyl lower alkyl group (that may have 1 to 2 lower alkyl groups on the pyrrolyl group as a substituent(s)), (xviii) a lower alkyl group substituted with a dihydropyrazolyl group that may have a single oxo group, (xix) a pyrazolyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrazolyl group), (xx) an imidazolyl lower alkyl group, (xxi) a pyridyl lower alkyl group, (xxii) a pyrazinyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrazinyl group), (xxiii) a pyrrolidinyl lower alkyl group (that may have 1 to 2 groups selected from the group consisting of an oxo group and a lower alkyl group as a substituent(s) on the pyrrolidinyl group), (xxiv) a piperidyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent(s) on the piperidyl group), (xxv) a piperazinyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the piperazinyl group), (xxvi) a morpholinyl lower alkyl group, (xxvii) a thienyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the thienyl group), (xxviii) a thiazolyl lower alkyl group, (xxix) a dihydrobenzofuryl lower alkyl group, (xxx) a benzopyranyl lower alkyl group (that may have a single oxo group as a substituent on the benzopyranyl group), (xxxi) a benzimidazolyl lower alkyl group, (xxxii) an indolyl lower alkyl group that may have 1 to 3 lower alkoxycarbonyl groups on the lower alkyl group, (xxxiii) an imidazolyl lower alkyl group that has 1 to 3 substituents selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group, on the lower alkyl group, (xxxiv) a pyridyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio lower alkyl group as a substituent(s), (xxxv) a pyrrolidinyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and a benzoyl group as a substituent(s), (xxxvi) a piperidyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent(s) on the phenyl group), (xxxvii) a tetrahydrofuryl group that may have a single oxo group (xxxviii) a hexahydroazepinyl group that may have a single oxo group, (xxxix) a pyrazolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a furyl group as a substituent(s), (xl) a thiazolyl group, (xli) a thiadiazolyl group that may have 1 to 3 lower alkyl groups, (xlii) an isoxazolyl group that may have 1 to 3 lower alkyl groups, (xliii) an indazolyl group, (xliv) an indolyl group, (xlv) a tetrahydrobenzothiazolyl group, (xlvi) a tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and an oxo group as a substituent(s), (xlvii) a quinolyl group that may have 1 to 3 lower alkyl groups, (xlviii) a benzodioxolyl lower alkyl group, (xlix) a phenyl group or naphthyl group that may have 1 to 3 groups as a substituent(s), selected from the group consisting of a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group, and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; a phenyloxy group; a phenyl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a phenyl group; a pyrazolyl group; a pyrrolidinyl group that may have a single oxo group; an oxazolyl group; an imidazolyl group that may have 1 to 3 lower alkyl groups; a dihydrofuryl group that may have a single oxo group; a thiazolidinyl lower alkyl group that may have two oxo groups; an imidazolyl lower alkanoyl group; and piperidinylcarbonyl group, (l) a cyano lower alkyl group, (li) a dihydroquinolyl group that may have 1 to 3 group(s) selected from the group consisting of a lower alkyl group and an oxo group, (lii) a halogen substituted lower alkylamino group, (liii) a lower alkylthio lower alkyl group, (liv) an amidino group that may have a lower alkyl group, (lv) an amidino lower alkyl group, (lvi) a lower alkenyloxy lower alkyl group, (lvii) a phenylamino group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, and a halogen substituted lower alkoxy group on the phenyl group, (lviii) a phenyl lower alkenyl group, (lix) a pyridylamino group that may have 1 to 3 lower alkyl groups, (lx) a phenyl lower alkyl group (that may have as a substituent(s) on the phenyl group and/or the lower alkyl group 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, carbamoyl group, and a lower alkoxycarbonyl group), (lxi) a lower alkynyl group, (lxii) a phenyloxy lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, N-lower alkoxy-N-lower alkylcarbamoyl group, and oxopyrrolidinyl group as a substituent(s) on the phenyl group), (lxiii) an isoxazolidinyl group that may have a single oxo group, (lxiv) a dihydroindenyl group, (lxv) a phenyl lower alkoxy lower alkyl group, (lxvi) a tetrahydropyranyl group, (lxvii) an azetidinyl group that may have 1 to 3 groups selected from the group consisting of a lower alkanoyl group and benzoyl group, (lxviii) an azetidinyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkanoyl group and benzoyl group, (lxix) a tetrazolyl group, (lxx) an indolinyl group that may have a single oxo group, (lxxi) a triazolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a lower alkylthio group, (lxxii) an imidazolyl group that may have 1 to 3 carbamoyl groups, (lxxiii) an oxazolyl group that may have 1 to 3 lower alkyl groups, (lxxiv) an isothiazolyl group that may have 1 to 3 lower alkyl groups, (lxxv) a benzimidazolyl group, (lxxvi) a dihydrobenzothiazolyl group that may have a single oxo group, (lxxvii) a thienyl group that may have 1 to 3 lower alkoxycarbonyl groups, and (lxxviii) an oxazolyl lower alkyl group that may have 1 to 3 lower alkyl groups, (29) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a benzoyl group, and an amino substituted alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the amino group) on the amino group, (30) a lower alkyl group substituted with a single carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group, (31) a thiocarbamoyl group that may have 1 to 2 lower alkyl groups, (32) a sulfamoyl group, (33) an oxazolidinyl group that may have a single oxo group, (34) an imidazolidinyl group that may have 1 to 2 substituents selected from the group consisting of an oxo group and a lower alkyl group, (35) a pyrrolidinyl group that may have a single oxo group, (36) an imidazolyl group, (37) a triazolyl group, (38) an isoxazolyl group, (39) a piperidyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkylphenylsulfonyl group, an oxo group, a hydroxy group, and an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and a lower alkanoylamino lower alkanoyl group, (40) a piperidylcarbonyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and a benzoyl group may be present), a piperidyl group (on which 1 to 3 groups selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group, and a benzoyl group may be present), a piperazinyl group (on which 1 to 3 lower alkyl groups may be present as a substituent(s)), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepynyl group (on which a single lower alkyl group may be present as a substituent), a pyridyl group, a pyridyloxy group, a pyridyl lower alkoxy group, a tetrahydroquinolyl group (on which a single oxo group may be present), a benzodioxolyl group, a phenyl lower alkoxy group (that may have on the phenyl group 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkoxy group), a phenyl group (on which 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group, and a hydroxy group may be present), phenyloxy group (that may have on the phenyl group 1 to 3 groups selected from the group consisting of a cyano group, a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), a phenyl lower alkyl group (on the phenyl group, 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group may be present), and a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl group), (41) a pyrrolidinylcarbonyl group that may have 1 to 3 groups as a substituent(s) selected from the group consisting of a hydroxy lower alkyl group, carbamoyl group, a hydroxy group, an amino group (that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, and a benzoyl group on the amino group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a single lower alkyl group as a substituent on the piperazinyl group), an amino lower alkyl group (that may have 1 to 2 lower alkyl groups present as a substituent(s) on the amino group), a phenyloxy group (that may have 1 to 3 halogen substituted lower alkoxy groups on the phenyl group), a phenyloxy lower alkyl group (that may have 1 to 3 halogen substituted lower alkoxy groups on the phenyl group), and a tetrahydroquinolyl group (on which an oxo group may be present), (42) a piperazinylcarbonyl group that may have 1 to 3 groups as a substituent(s) selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the amino group), a piperidyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxoranyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have 1 to 2 phenyl groups as a substituent(s) on the lower alkyl group), an imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group (that may have 1 to 2 lower alkyl groups as a substituent(s)), a pyridyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a cyano group, and a halogen substituted lower alkyl group as a substituent(s)), a thieno[2,3-b]pyridyl group, a phenyl group (on which 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group may be present), a benzoyl group, a furyl carbonyl group, a phenyl lower alkoxycarbonyl group, and an oxo group, (43) a hexahydroazepinylcarbonyl group, (44) a hexahydro-1,4-diazepinylcarbonyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group and a pyridyl group, (45) a dihydropyrroylcarbonyl group that may have 1 to 3 lower alkyl groups, (46) a thiomorpholinylcarbonyl group, (47) a morpholinylcarbonyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group, and a phenyl group, (48) a thiazolidinyl cabonyl group that may have 1 to 3 phenyl groups that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a cyano group, (49) an azabicyclo[3.2.2]nonylcarbonyl group, (50) an 8-azabicyclo[3.2.1]octylcarbonyl group that may have 1 to 3 halogen substituted or unsubstituted phenyloxy groups, (51) an indolinylcarbonyl group, (52) a tetrahydroquinolylcarbonyl group, (53) a tetrahydropyrido[3.4-b]indolylcarbonyl group, (54) a morpholinyl lower alkyl group, (55) a piperazinyl lower alkyl group that may have 1 to 3 lower alkyl groups on the piperazinyl group, (56) a morpholinylcarbonyl lower alkyl group, (57) a piperazinylcarbonyl lower alkyl group that may have 1 to 3 lower alkyl groups on the piperazinyl group, (58) an oxo group, (59) an amino lower alkoxy group (that may have 1 to 2 lower alkyl groups on the amino group), (60) a lower alkoxy lower alkoxy group, (61) a piperazinyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group, and a lower alkoxycarbonyl group, (62) a morpholinyl group, (63) a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have 1 to 3 groups selected from the group consisting of an oxo group and a phenyl group, (64) a tetrahydropyridylcarbonyl group that may have 1 to 3 pyridyl groups, (65) an imidazolidinylcarbonyl group that may have a single thioxo group, and (66) a 1,4-dioxa-8-azaspiro{4.5}decanyl group.
 3. The compound according to claim 1, wherein A is a lower alkylene group.
 4. The compound according to claim 3, wherein R¹ represents a heterocyclic group selected from the group consisting of a pyrrolidinyl group, a piperidyl group, a pyrazolyl group, a pyridyl group, pyrimidinyl group, and a thiazolyl group, and on the heterocyclic group represented by R¹, 1 to 5 groups selected from the group consisting of (1) to (66) below may be present as a substituent(s): (1) a lower alkyl group, (2) a lower alkenyl group, (3) a halogen substituted lower alkyl group, (4) a lower alkoxy group, (5) a phenoxy group, (6) a lower alkylthio group, (7) a halogen substituted lower alkoxy group, (8) a hydroxy group, (9) a phenyl lower alkoxy group, (10) a hydroxy lower alkyl group, (11) a lower alkoxy lower alkyl group, (12) a halogen atom, (13) a cyano group, (14) a phenyl group, (15) a nitro group, (16) an amino group, (17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group, and a lower alkoxycarbonylamino lower alkanoyl group as a substituent(s), (18) a lower alkanoyl group, (19) a phenylsulfonyl group that may have a single lower alkyl group on the phenyl group, (20) a carboxy group, (21) a lower alkoxycarbonyl group, (22) a carboxy lower alkyl group, (23) a lower alkoxycarbonyl lower alkyl group, (24) a lower alkanoylamino lower alkanoyl group, (25) a carboxy lower alkenyl group, (26) a lower alkoxycarbonyl lower alkenyl group, (27) a carbamoyl lower alkenyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a lower alkyl group substituted with 1 to 3 halogen atoms as a substituent(s), (28) a carbamoyl group that may have 1 to 2 groups selected from the group consisting of the groups (i) to (lxxviii) below as a substituent(s): (i) a lower alkyl group, (ii) a lower alkoxy group, (iii) a hydroxy lower alkyl group, (iv) a lower alkoxy lower alkyl group, (v) an phenoxy lower alkyl group, (vi) a halogen substituted lower alkyl group, (vii) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a benzoyl group, and a carbamoyl group, (viii) a cyclo C3-C8 alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group, and a phenyl lower alkoxy group as a substituent(s), (ix) a cyclo C3-C8 alkyl substituted lower alkyl group, (x) a lower alkenyl group, (xi) a lower alkyl group having 1 to 2 carbamoyl groups that may have 1 to 2 groups as a substituent(s) selected from the group consisting of a lower alkyl group, a phenyl group that may have a single lower alkyl group, and a phenyl group that may have a single lower alkoxy group, (xii) a lower alkyl group having 1 to 2 lower alkoxy carbonyl groups, (xiii) a furyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the furyl group), (xiv) a tetrahydrofuryl lower alkyl group, (xv) a 1,3-dioxolanyl lower alkyl group, (xvi) a tetrahydropyranyl lower alkyl group, (xvii) a pyrrolyl lower alkyl group (that may have 1 to 2 lower alkyl groups on the pyrrolyl group as a substituent(s)), (xviii) a lower alkyl group substituted with a dihydropyrazolyl group that may have a single oxo group, (xix) a pyrazolyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrazolyl group), (xx) an imidazolyl lower alkyl group, (xxi) a pyridyl lower alkyl group, (xxii) a pyrazinyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the pyrazinyl group), (xxiii) a pyrrolidinyl lower alkyl group (that may have 1 to 2 groups selected from the group consisting of an oxo group and a lower alkyl group as a substituent(s) on the pyrrolidinyl group), (xxiv) a piperidyl lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent(s) on the piperidyl group), (xxv) a piperazinyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the piperazinyl group), (xxvi) a morpholinyl lower alkyl group, (xxvii) a thienyl lower alkyl group (that may have 1 to 3 lower alkyl groups as a substituent(s) on the thienyl group), (xxviii) a thiazolyl lower alkyl group, (xxix) a dihydrobenzofuryl lower alkyl group, (xxx) a benzopyranyl lower alkyl group (that may have a single oxo group as a substituent on the benzopyranyl group), (xxxi) a benzimidazolyl lower alkyl group, (xxxii) an indolyl lower alkyl group that may have 1 to 3 lower alkoxycarbonyl groups on the lower alkyl group, (xxxiii) an imidazolyl lower alkyl group that has 1 to 3 substituents selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group, on the lower alkyl group, (xxxiv) a pyridyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio lower alkyl group as a substituent(s), (xxxv) a pyrolidinyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and a benzoyl group as a substituent(s), (xxxvi) a piperidyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a halogen atom as a substituent(s) on the phenyl group), (xxxvii) a tetrahydrofuryl group that may have a single oxo group (xxxviii) a hexahydroazepinyl group that may have a single oxo group, (xxxix) a pyrazolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a phenyl group, and a furyl group as a substituent(s), (xl) a thiazolyl group, (xli) a thiadiazolyl group that may have 1 to 3 lower alkyl groups, (xlii) an isoxazolyl group that may have 1 to 3 lower alkyl groups, (xliii) an indazolyl group, (xliv) an indolyl group, (xlv) a tetrahydrobenzothiazolyl group, (xlvi) a tetrahydroquinolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and an oxo group as a substituent(s), (xlvii) a quinolyl group that may have 1 to 3 lower alkyl groups, (xlviii) a benzodioxolyl lower alkyl group, (xlix) a phenyl group or naphthyl group that may have 1 to 3 groups as a substituent(s), selected from the group consisting of a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group, and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; a phenyloxy group; a phenyl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a phenyl group; a pyrazolyl group; a pyrrolidinyl group that may have a single oxo group; an oxazolyl group; an imidazolyl group that may have 1 to 3 lower alkyl groups; a dihydrofuryl group that may have a single oxo group; a thiazolidinyl lower alkyl group that may have two oxo groups; an imidazolyl lower alkanoyl group; and piperidinylcarbonyl group, (l) a cyano lower alkyl group, (li) a dihydroquinolyl group that may have 1 to 3 group(s) selected from the group consisting of a lower alkyl group and an oxo group, (lii) a halogen substituted lower alkylamino group, (liii) a lower alkylthio lower alkyl group, (liv) an amidino group that may have a lower alkyl group, (lv) an amidino lower alkyl group, (lvi) a lower alkenyloxy lower alkyl group, (lvii) a phenylamine group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, and a halogen substituted lower alkoxy group on the phenyl group, (lviii) a phenyl lower alkenyl group, (lix) a pyridylamino group that may have 1 to 3 lower alkyl groups, (lx) a phenyl lower alkyl group (that may have as a substituent(s) on the phenyl group and/or the lower alkyl group 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, carbamoyl group, and a lower alkoxycarbonyl group), (lxi) a lower alkynyl group, (lxii) a phenyloxy lower alkyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group, N-lower alkoxy-N-lower alkylcarbamoyl group, and oxopyrrolidinyl group as a substituent(s) on the phenyl group), (lxiii) an isoxazolidinyl group that may have a single oxo group, (lxiv) a dihydroindenyl group, (lxv) a phenyl lower alkoxy owe alkyl group, (lxvi) a tetrahydropyranyl group, (lxvii) an azetidinyl group that may have 1 to 3 groups selected from the group consisting of a lower alkanoyl group and benzoyl group, (lxviii) an azetidinyl lower alkyl group that may have 1 to 3 groups selected from the group consisting of a lower alkanoyl group and benzoyl group, (lxix) a tetrazolyl group, (lxx) an indolinyl group that may have a single oxo group, (lxxi) a triazolyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group and a lower alkylthio group, (lxxii) an imidazolyl group that may have 1 to 3 carbamoyl groups, (lxxiii) an oxazolyl group that may have 1 to 3 lower alkyl groups, (lxxiv) an isothiazolyl group that may have 1 to 3 lower alkyl groups, (lxxv) a benzimidazolyl group, (lxxvi) a dihydrobenzothiazolyl group that may have a single oxo group, (lxxvii) a thienyl group that may have 1 to 3 lower alkoxycarbonyl groups, and (lxxviii) an oxazolyl lower alkyl group that may have 1 to 3 lower alkyl groups, (29) an amino lower alkyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a benzoyl group, and an amino substituted alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the amino group) on the amino group, (30) a lower alkyl group substituted with a single carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group, (31) a thiocarbamoyl group that may have 1 to 2 lower alkyl groups, (32) a sulfamoyl group, (33) an oxazolidinyl group that may have a single oxo group, (34) an imidazolidinyl group that may have 1 to 2 substituents selected from the group consisting of an oxo group and a lower alkyl group, (35) a pyrrolidinyl group that may have a single oxo group, (36) an imidazolyl group, (37) a triazolyl group, (38) an isoxazolyl group, (39) a piperidyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkylphenylsulfonyl group, an oxo group, a hydroxy group, and an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and a lower alkanoylamino lower alkanoyl group, (40) a piperidylcarbonyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and a benzoyl group may be present), a piperidyl group (on which 1 to 3 groups selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group, and a benzoyl group may be present), a p perazinyl group (on which 1 to 3 lower alkyl groups may be present as a substituent(s)), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepynyl group (on which a single lower alkyl group may be present as a substituent), a pyridyl group, a pyridyloxy group, a pyridyl lower alkoxy group, a tetrahydroquinolyl group (on which a single oxo group may be present), a benzodioxolyl group, a phenyl lower alkoxy group (that may have on the phenyl group 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkoxy group), a phenyl group (on which 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group, and a hydroxy group may be present), phenyloxy group (that may have on the phenyl group 1 to 3 groups selected from the group consisting of a cyano group, a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), a phenyl lower alkyl group (on the phenyl group, 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group may be present), and a benzoyl group (that may have 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkoxy group on the phenyl group), (41) a pyrrolidinylcarbonyl group that may have 1 to 3 groups as a substituent(s) selected from the group consisting of a hydroxy lower alkyl group, carbamoyl group, a hydroxy group, an amino group (that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, and a benzoyl group on the amino group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a single lower alkyl group as a substituent on the piperazinyl group), an amino lower alkyl group (that may have 1 to 2 lower alkyl groups present as a substituent(s) on the amino group), a phenyloxy group (that may have 1 to 3 halogen substituted lower alkoxy groups on the phenyl group), a phenyloxy lower alkyl group (that may have 1 to 3 halogen substituted lower alkoxy groups on the phenyl group), and a tetrahydroquinolyl group (on which an oxo group may be present), (42) a piperazinylcarbonyl group that may have 1 to 3 groups as a substituent(s) selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the amino group), a piperidyl lower alkyl group (that may have 1 to 2 lower alkyl groups as a substituent(s) on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxoranyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have 1 to 2 phenyl groups as a substituent(s) on the lower alkyl group), an imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group (that may have 1 to 2 lower alkyl groups as a substituent(s)), a pyridyl group (that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a cyano group, and a halogen substituted lower alkyl group as a substituent(s)), a thieno[2,3-b]pyridyl group, a phenyl group (on which 1 to 3 groups selected from the group consisting of a halogen atom and a lower alkyl group may be present), a benzoyl group, a furyl carbonyl group, a phenyl lower alkoxycarbonyl group, and an oxo group, (43) a hexahydroazepinylcarbonyl group, (44) a hexahydro-1,4-diazepinylcarbonyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group and a pyridyl group, (45) a dihydropyrrolylcarbonyl group that may have 1 to 3 lower alkyl groups, (46) a thiomorpholinylcarbonyl group, (47) a morpholinylcarbonyl group that may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group, and a phenyl group, (48) a thiazolidinyl cabonyl group that may have 1 to 3 phenyl groups that may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a cyano group, (49) an azabicyclo[3.2.2]nonylcarbonyl group, (50) an 8-azabicyclo[3.2.1]octylcarbonyl group that may have 1 to 3 halogen substituted or unsubstituted phenyloxy groups, (51) an indolinylcarbonyl group, (52) a tetrahydroquinolylcarbonyl group, (53) a tetrahydropyrido[3,4-b]indolylcarbonyl group, (54) a morpholinyl lower alkyl group, (55) a piperazinyl lower alkyl group that may have 1 to 3 lower alkyl groups on the piperazinyl group, (56) a morpholinylcarbonyl lower alkyl group, (57) a piperazinylcarbonyl lower alkyl group that may have 1 to 3 lower alkyl groups on the piperazinyl group, (58) an oxo group, (59) an amino lower alkoxy group (that may have 1 to 2 lower alkyl groups on the amino group), (60) a lower alkoxy lower alkoxy group, (61) a piperazinyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group, and a lower alkoxycarbonyl group, (62) a morpholinyl group, (63) a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have 1 to 3 groups selected from the group consisting of an oxo group and a phenyl group, (64) a tetrahydropyridylcarbonyl group that may have 1 to 3 pyridyl groups, (65) an imidazolidinylcarbonyl group that may have a single thioxo group, and (66) a 1,4-dioxa-8-azaspiro[4.5]decanyl group.
 5. The compound according to claim 4, wherein R¹ represents a heterocyclic group selected from the group consisting of a pyrrolidinyl group, a piperidyl group, a pyrazolyl group, a pyridyl group, a pyrimidinyl group, and a thiazolyl group, and on the heterocyclic group represented by R¹, 1 to 5 groups selected from the group consisting of (1), (4), (10), (17), (18), (21), (28), (29), (30), (33), (34), (35), (36), (39), (61), and (62) shown below may be present as a substituent(s): (1) a lower alkyl group, (4) a lower alkoxy group, (10) a hydroxy lower alkyl group, (17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group, and a lower alkoxycarbonylamino lower alkanoyl group, as a substituent(s), (18) a lower alkanoyl group, (21) a lower alkoxycarbonyl group, (28) a carbamoyl group that may have 1 to 2 groups selected from the group consisting of the groups (i), (ii), (iv), (xii) and (xxi) below as a substituent(s): (i) a lower alkyl group, (ii) a lower alkoxy group, (iv) a lower alkoxy lower alkyl group, (xii) a lower alkyl group having 1 to 2 lower alkoxy carbonyl groups, and (xxi) a pyridyl lower alkyl group, (29) an amino lower alkyl group that may have, on the amino group, 1 to 2 groups selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, a phenyl group, a phenyl lower alkyl group, a benzoyl group, and an amino substituted lower alkyl group (which may have 1 to 2 lower alkyl groups may be present as a substituents) on the amino group), (30) a lower alkyl group substituted with a single carbamoyl group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group, (33) an oxazolidinyl group that may have a single oxo group, (34) an imidazolidinyl group that may have 1 to 2 substituents selected from the group consisting of an oxo group and a lower alkyl group, (35) a pyrrolidinyl group that may have a single oxo group, (36) an imidazolyl group, (39) a piperidyl group that may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkyl phenylsulfonyl group, an oxo group, hydroxy group, and an amino group that may have 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and a lower alkanoylamino lower alkanoyl group, (61) a piperazinyl group that may have 1 to 3 groups selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group, and a lower alkoxycarbonyl group, and (62) a morpholinyl group.
 6. The compound according to claim 5, wherein R¹ represents a heterocyclic group selected from the group consisting of a piperidyl group, pyrazolyl group, and thiazolyl group, and, on the heterocyclic group represented by R¹, 1 to 3 groups selected from the group consisting of (1), (4), (10), (17), (18), (21), (28), (29), (30), (33), (34), (35), (36), (39), (61), and (62) defined in claim 5 may be present as a substituent(s).
 7. The compound according to claim 6, wherein R¹ represents a heterocyclic group selected from a piperidyl group, pyrazolyl group, and thiazolyl group, and, on the heterocyclic group represented by R¹, 1 to 3 groups selected from the group consisting of (1), (17), and (28) shown below may be present as a substituent(s): (1) a lower alkyl group; (17) an amino group having 1 to 2 groups selected from the group consisting of a lower alkyl group and a lower alkanoyl group, as a substituent(s); and (28) a carbamoyl group that may have 1 to 2 lower alkyl groups.
 8. The compound according to claim 7, wherein R¹ represents a pyrazolyl group having a single lower alkyl group and a single lower alkanoyl amino group; a pyrazolyl group having a single lower alkyl group and a single N,N-di-lower alkyl amino group; a piperidyl group having a single N,N-di-lower alkyl carbamoyl group; or a thiazolyl group having a single N,N-di-lower alkyl carbamoyl group.
 9. A process for producing a heterocyclic compound represented by formula (1):

or a salt thereof, where R² represents a hydrogen atom or a lower alkyl group; A represents a lower alkylene group or a lower alkenylene group; and R¹ represents a heterocyclic group selected from the group consisting of a pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, isoxazolyl group, thiazolyl group, and thienyl group; wherein at least one group selected from the group consisting of the groups (1) to (66) below may be present as a substituent on the heterocyclic group represented by R¹: (1) a lower alkyl group, (2) a lower alkenyl group, (3) a halogen substituted lower alkyl group, (4) a lower alkoxy group, (5) an aryloxy group, (6) a lower alkylthio group, (7) a halogen substituted lower alkoxy group, (8) a hydroxy group, (9) a protected hydroxy group, (10) a hydroxy lower alkyl group, (11) a protected hydroxy lower alkyl group, (12) a halogen atom, (13) a cyano group, (14) an aryl group, (15) a nitro group, (16) an amino group, (17) an amino group having a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group, and a lower alkoxy carbonylamino lower alkanoyl group as a substituent, (18) a lower alkanoyl group, (19) an arylsulfonyl group that may have a lower alkyl group(s) on the aryl group, (20) a carboxy group, (21) a lower alkoxycarbonyl group, (22) a carboxy lower alkyl group, (23) a lower alkoxycarbonyl lower alkyl group, (24) a lower alkanoylamino lower alkanoyl group, (25) a carboxy lower alkenyl group, (26) a lower alkoxycarbonyl lower alkenyl group, (27) a carbamoyl lower alkenyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group as a substituent, (28) a carbamoyl group that may have a group(s) selected from the group consisting of the groups (i) to (lxxviii) below as a substituent: (i) a lower alkyl group, (ii) a lower alkoxy group, (iii) a hydroxy lower alkyl group, (iv) a lower alkoxy lower alkyl group, (v) an aryloxy lower alkyl group, (vi) a halogen substituted lower alkyl group, (vii) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an aroyl group, and a carbamoyl group, (viii) a cyclo C3-C8 alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group, and a phenyl lower alkoxy group as a substituent, (ix) a cyclo C3-C8 alkyl substituted lower alkyl group, (x) a lower alkenyl group, (xi) a carbamoyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, phenyl group that may have a lower alkyl group(s), and a phenyl group(s) that may have a lower alkoxy group(s) as a substituent, (xii) a lower alkoxycarbonyl lower alkyl group, (xiii) a furyl lower alkyl group (that may have a lower alkyl group(s) as a substituent) on the furyl group, (xiv) a tetrahydrofuryl lower alkyl group, (xv) a 1,3-dioxolanyl lower alkyl group, (xvi) a tetrahydropyranyl lower alkyl group, (xvii) a pyrrolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrrolyl group), (xviii) a lower alkyl group substituted with a dihydropyrazolyl group that may have an oxo group(s), (xix) a pyrazolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazolyl group), (xx) an imidazolyl lower alkyl group, (xxi) a pyridyl lower alkyl group, (xxii) a pyrazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazinyl group), (xxiii) a pyrrolidinyl lower alkyl group (that may have a group(s) selected from the group consisting of an oxo group(s) and a lower alkyl group as a substituent on the pyrrolidinyl group), (xxiv) a piperidyl lower alkyl group (that may have a group(s) selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent on the piperidyl group), (xxv) a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group), (xxvi) a morpholinyl lower alkyl group, (xxvii) a thienyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the thienyl group), (xxviii) a thiazolyl lower alkyl group, (xxix) a dihydrobenzofuryl lower alkyl group, (xxx) a benzopyranyl lower alkyl group (that may have an oxo group(s) as a substituent on the benzopyranyl group), (xxxi) a benzimidazolyl lower alkyl group, (xxxii) an indolyl lower alkyl group that may have a lower alkoxycarbonyl group(s) on the lower alkyl group, (xxxiii) an imidazolyl lower alkyl group that has a substituent(s) selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group on the lower alkyl group, (xxxiv) a pyridyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio lower alkyl group as a substituent, (xxxv) a pyrrolidinyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and an aroyl group as a substituent, (xxxvi) a piperidyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and an aroyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen atom as a substituent, (xxxvii) a tetrahydrofuryl group that may have an oxo group(s), (xxxviii) a hexahydroazepinyl group that may have an oxo group(s), (xxxix) a pyrazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, an aryl group, and a furyl group as a substituent, (xl) a thiazolyl group, (xli) a thiadiazolyl group that may have a lower alkyl group(s), (xlii) an isoxazolyl group that may have a lower alkyl group(s), (xliii) an indazolyl group, (xliv) an indolyl group, (xlv) a tetrahydrobenzothiazolyl group, (xlvi) a tetrahydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and an oxo group as a substituent, (xlvii) a quinolyl group that may have a lower alkyl group(s), (xlviii) a benzodioxolyl lower alkyl group, (xlix) an aryl group that may have a group(s) as a substituent, selected from the group consisting of a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group, and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; an aryloxy group; an aryl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an aryl group; a pyrazolyl group; a pyrrolidinyl group that may have an oxo group(s); an oxazolyl group; an imidazolyl group that may have a lower alkyl group(s); a dihydrofuryl group that may have an oxo group(s); a thiazolidinyl lower alkyl group that may have an oxo group(s); an imidazolyl lower alkanoyl group; and a piperidinylcarbonyl group, (l) a cyano lower alkyl group, (li) a dihydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an oxo group, (lii) a halogen substituted lower alkylamino group, (liii) a lower alkylthio lower alkyl group, (liv) an amidino group that may have a lower alkyl group(s), (lv) an amidino lower alkyl group, (lvi) a lower alkenyloxy lower alkyl group, (lvii) an arylamino group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, and a halogen substituted lower alkoxy group, on the aryl group, (lviii) an aryl lower alkenyl group, (lix) a pyridylamino group that may have a lower alkyl group(s), (lx) an aryl lower alkyl group (that may have on the aryl group and/or the lower alkyl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, a carbamoyl group, and a lower alkoxycarbonyl group as a substituent), (lxi) a lower alkynyl group, (lxii) an aryloxy lower alkyl group (that may have as a substituent on the aryl group a group(s) selected from the group consisting of a lower alkoxy group, a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkoxy group and a lower alkyl group, and a pyrrolidinyl group that may have an oxo group(s)), (lxiii) an isoxazolidinyl group that may have an oxo group(s), (lxiv) a dihydroindenyl group, (lxv) an aryl lower alkoxy lower alkyl group, (lxvi) a tetrahydropyranyl group, (lxvii) an azetidinyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and an aroyl group, (lxviii) an azetidinyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and aroyl group, (lxix) a tetrazolyl group, (lxx) an indolinyl group that may have an oxo group(s), (lxxi) a triazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a lower alkylthio group, (lxxii) an imidazolyl group that may have a carbamoyl group(s), (lxxiii) an oxazolyl group that may have a lower alkyl group(s), (lxxiv) an isothiazolyl group that may have a lower alkyl group(s), (lxxv) a benzimidazolyl group, (lxxvi) a dihydrobenzothiazolyl group that may have an oxo group(s), (lxxvii) a thienyl group that may have a lower alkoxycarbonyl group(s), and (lxxviii) an oxazolyl lower alkyl group that may have a lower alkyl group(s), (29) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, an aryl group, an aryl lower alkyl group, an aroyl group, and an amino substituted alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group) on the amino group, (30) a lower alkyl group substituted with a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group, (31) a thiocarbamoyl group that may have a lower alkyl group(s), (32) a sulfamoyl group, (33) an oxazolidinyl group that may have an oxo group(s), (34) an imidazolidinyl group that may have a substituent(s) selected from the group consisting of an oxo group and a lower alkyl group, (35) a pyrrolidinyl group that may have an oxo group(s), (36) an imidazolyl group, (37) a triazolyl group, (38) an isoxazolyl group, (39) a piperidyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an arylsulfonyl group, an oxo group, a hydroxy group, and an amino group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and lower alkanoylamino lower alkanoyl group, (40) a piperidylcarbonyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and an aroyl group may be present), a piperidyl group (on which a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group, and an aroyl group may be present), a piperazinyl group (on which a lower alkyl group(s) may be present as a substituent), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepinyl group (on which a lower alkyl group(s) may be present as a substituent), a pyridyl group, a pyridyloxy group, a pyridyl lower alkoxy group, a tetrahydroquinolyl group (on which an oxo group(s) may be present), a benzodioxolyl group, an aryl lower alkoxy group (that may have a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkoxy group on the aryl group), an aryl group (on which a group(s) selected from the group consisting of a halogen atom, a lower alkoxy group, and a hydroxy group may be present), an aryloxy group (that may have on the aryl group a group(s) selected from the group consisting of a cyano group, a halogen atom, lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), an aryl lower alkyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), and an aroyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom and a lower alkoxy group), (41) a pyrrolidinylcarbonyl group that may have a group as a substituent, selected from the group consisting of a hydroxy lower alkyl group, a carbamoyl group, a hydroxy group, an amino group (that may have on the amino group a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, and an aroyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group), an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), an aryloxy group (that may have a halogen substituted lower alkoxy group(s) on the aryl group), an aryloxy lower alkyl group (that may have a halogen substituted lower alkoxy group(s) on the aryl group), and a tetrahydroquinolyl group (on which an oxo group(s) may be present), (42) a piperazinylcarbonyl group that may have a group(s) as a substituent, selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), a piperidyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxolanyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have a phenyl group(s) as a substituent on the lower alkyl group), a imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group (that may have a lower alkyl group(s) as a substituent), pyridyl group (that may have on the pyridyl group a group(s) selected from the group consisting of a lower alkyl group, a cyano group, and a halogen substituted lower alkyl group as a substituent), a thieno[2,3-b]pyridyl group, an aryl group (on which a group(s) selected from the group consisting of a halogen atom and a lower alkyl group may be present), an aroyl group, a furyl carbonyl group, an aryl lower alkoxycarbonyl group, and an oxo group, (43) a hexahydroazepinylcarbonyl group, (44) a hexahydro-1,4-diazepinylcarbonyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and a pyridyl group, (45) a dihydropyrrolylcarbonyl group that may have a lower alkyl group(s), (46) a thiomorpholinylcarbonyl group, (47) a morpholinylcarbonyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group, and an aryl group, (48) a thiazolidinyl carbonyl group that may have an aryl group(s) that may have a group(s) selected from the group consisting of a lower alkoxy group and a cyano group, (49) an azabicyclo[3.2,2]nonylcarbonyl group, (50) an 8-azabicyclo[3,2.1]octylcarbonyl group that may have a halogen substituted or unsubstituted aryloxy group(s), (51) an indolinylcarbonyl group, (52) a tetrahydroquinolylcarbonyl group, (53) a tetrahydropyrido[3.4-b]indolylcarbonyl group, (54) a morpholinyl lower alkyl group, (55) a piperazinyl lower alkyl group that may have a lower alkyl group(s) on the piperazinyl group, (56) a morpholinylcarbonyl lower alkyl group, (57) a piperazinylcarbonyl lower alkyl group that may have a lower alkyl group(s) on the piperazinyl group, (58) an oxo group, (59) an amino lower alkoxy group (that may have a lower alkyl group(s) on the amino group), (60) a lower alkoxy lower alkoxy group, (61) a piperazinyl group that may have a group(s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group, and a lower alkoxycarbonyl group, (62) a morpholinyl group, (63) a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have a group(s) selected from the group consisting of an oxo group and an aryl group, (64) a tetrahydropyridylcarbonyl group that may have a pyridyl group(s), (65) an imidazolidinylcarbonyl group that may have a thioxo group(s), and (66) a 1,4-dioxa-8-azaspiro[4.5]decanyl group; said process comprising reacting a compound represented by the formula: R₁—O-A-X₁ [wherein R₁ and A are the same as defined above, and X₁ represents a halogen atom or a group which causes the same substitution reaction as a halogen atom] or a salt thereof with a compound represented by the formula:

[wherein R₂ is the same as defined above] or a salt thereof.
 10. A pharmaceutical composition comprising a heterocylic compound of formula (1) or a salt thereof according to any one of claims 1 to 4, 5, and 6 to 8, and a pharmaceutically acceptable carrier for treating a central nervous system disorder selected from the group consisting of schizophrenia; bipolar I type disorder; bipolar II type disorder; depression; endogenous depression; major depression; melancholy and refractory depression; and autism disorder (autism).
 11. A process for producing a pharmaceutical composition comprising mixing a heterocyclic compound of formula (1) or a salt thereof according to any one of claims 1 to 4, 5, and 6 to 8 with a pharmaceutically acceptable carrier.
 12. A method for treating a central nervous system disorder selected from the group consisting of schizophrenia; bipolar I type disorder; bipolar II type disorder; depression; endogenous depression; major depression; and melancholy and refractory depression comprising administering to a human or an animal a heterocyclic compound of formula (1)

or a salt thereof, where R² represents a hydrogen atom or a lower alkyl group; A represents a lower alkylene group or a lower alkenylene group; and R¹ represents a heterocyclic group selected from the group consisting of a pyrrolidinyl group, piperidyl group, pyrazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, isoxazolyl group, thiazolyl group, and thienyl group wherein at least one group selected from the group consisting of the groups (1) to (66) below may be present as a substituent on the heterocyclic group represented by R¹: (1) a lower alkyl group, (2) a lower alkenyl group, (3) a halogen substituted lower alkyl group, (4) a lower alkoxy group, (5) an aryloxy group, (6) a lower alkylthio group, (7) a halogen substituted lower alkoxy group, (8) a hydroxy group, (9) a protected hydroxy group, (10) a hydroxy lower alkyl group, (11) a protected hydroxy lower alkyl group, (12) a halogen atom, (13) a cyano group, (14) an aryl group, (15) a nitro group, (16) an amino group, (17) an amino group having a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, a carbamoyl group, a lower alkyl carbamoyl group, an amino lower alkanoyl group, a lower alkanoylamino lower alkanoyl group, and a lower alkoxy carbonylamino lower alkanoyl group as a substituent, (18) a lower alkanoyl group, (19) an arylsulfonyl group that may have a lower alkyl group(s) on the aryl group, (20) a carboxy group, (21) a lower alkoxycarbonyl group, (22) a carboxy lower alkyl group, (23) a lower alkoxycarbonyl lower alkyl group, (24) a lower alkanoylamino lower alkanoyl group, (25) a carboxy lower alkenyl group, (26) a lower alkoxycarbonyl lower alkenyl group, (27) a carbamoyl lower alkenyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group as a substituent, (28) a carbamoyl group that may have a group(s) selected from the group consisting of the groups (i) to (lxxviii) below as a substituent: (i) a lower alkyl group, (ii) a lower alkoxy group, (iii) a hydroxy lower alkyl group, (iv) a lower alkoxy lower alkyl group, (v) an aryloxy lower alkyl group, (vi) a halogen substituted lower alkyl group, (vii) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an aroyl group, and a carbamoyl group, (viii) a cyclo C3-C8 alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxycarbonyl group, and a phenyl lower alkoxy group as a substituent, (ix) a cyclo C3-C8 alkyl substituted lower alkyl group, (x) a lower alkenyl group, (xi) a carbamoyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, phenyl group that may have a lower alkyl group(s), and a phenyl group(s) that may have a lower alkoxy group(s) as a substituent, (xii) a lower alkoxycarbonyl lower alkyl group, (xiii) a furyl lower alkyl group (that may have a lower alkyl group(s) as a substituent) on the furyl group, (xiv) a tetrahydrofuryl lower alkyl group, (xv) a 1,3-dioxolanyl lower alkyl group, (xvi) a tetrahydropyranyl lower alkyl group, (xvii) a pyrrolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrrolyl group), (xviii) a lower alkyl group substituted with a dihydropyrazolyl group that may have an oxo group(s), (xix) a pyrazolyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazolyl group), (xx) an imidazolyl lower alkyl group, (xxi) a pyridyl lower alkyl group, (xxii) a pyrazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the pyrazinyl group), (xxiii) a pyrrolidinyl lower alkyl group (that may have a group(s) selected from the group consisting of an oxo group(s) and a lower alkyl group as a substituent on the pyrrolidinyl group), (xxiv) a piperidyl lower alkyl group (that may have a group(s) selected from the group consisting of a benzoyl group and a lower alkanoyl group as a substituent on the piperidyl group), (xxv) a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group), (xxvi) a morpholinyl lower alkyl group, (xxvii) a thienyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the thienyl group), (xxviii) a thiazolyl lower alkyl group, (xxix) a dihydrobenzofuryl lower alkyl group, (xxx) a benzopyranyl lower alkyl group (that may have an oxo group(s) as a substituent on the benzopyranyl group, (xxxi) a benzimidazolyl lower alkyl group, (xxxii) an indolyl lower alkyl group that may have a lower alkoxycarbonyl group(s) on the lower alkyl group, (xxxiii) an imidazolyl lower alkyl group that has a substituent(s) selected from the group consisting of a carbamoyl group and a lower alkoxycarbonyl group on the lower alkyl group, (xxxiv) a pyridyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, and a lower alkylthio lower alkyl group as a substituent, (xxxv) a pyrrolidinyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and an aroyl group as a substituent, (xxxvi) a piperidyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, and an aroyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen atom as a substituent, (xxxvii) a tetrahydrofuryl group that may have an oxo group(s), (xxxviii) a hexahydroazepinyl group that may have an oxo group(s), (xxxix) a pyrazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, an aryl group, and a furyl group as a substituent, (xl) a thiazolyl group, (xli) a thiadiazolyl group that may have a lower alkyl group(s), (xlii) an isoxazolyl group that may have a lower alkyl group(s), (xliii) an indazolyl group, (xliv) an indolyl group, (xlv) a tetrahydrobenzothiazolyl group, (xlvi) a tetrahydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, and an oxo group as a substituent, (xlvii) a quinolyl group that may have a lower alkyl group(s), (xlviii) a benzodioxolyl lower alkyl group, (xlix) an aryl group that may have a group(s) as a substituent, selected from the group consisting of a halogen atom; a lower alkyl group; a lower alkoxy group; a halogen substituted lower alkyl group; a halogen substituted lower alkoxy group; a lower alkenyl group; an amino group that may have a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkyl sulfonyl group, a lower alkyl group, and an aryl group; a sulfamoyl group; a lower alkylthio group; a lower alkanoyl group; a lower alkoxycarbonyl group; a pyrrolyl group; a lower alkynyl group; a cyano group; a nitro group; an aryloxy group; an aryl lower alkoxy group; a hydroxy group; a hydroxy lower alkyl group; a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an aryl group; a pyrazolyl group; a pyrrolidinyl group that may have an oxo group(s); an oxazolyl group; an imidazolyl group that may have a lower alkyl group(s); a dihydrofuryl group that may have an oxo group(s); a thiazolidinyl lower alkyl group that may have an oxo group(s); an imidazolyl lower alkanoyl group; and a piperidinylcarbonyl group, (l) a cyano lower alkyl group, (li) a dihydroquinolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and an oxo group, (lii) a halogen substituted lower alkylamino group, (liii) a lower alkylthio lower alkyl group, (liv) an amidino group that may have a lower alkyl group(s), (lv) an amidino lower alkyl group, (lvi) a lower alkenyloxy lower alkyl group, (lvii) an arylamino group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen substituted lower alkyl group, and a halogen substituted lower alkoxy group, on the aryl group, (lviii) an aryl lower alkenyl group, (lix) a pyridylamino group that may have a lower alkyl group(s), (lx) an aryl lower alkyl group (that may have on the aryl group and/or the lower alkyl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a halogen substituted lower alkyl group, a halogen substituted lower alkoxy group, a lower alkoxy group, a carbamoyl group, and a lower alkoxycarbonyl group as a substituent), (lxi) a lower alkynyl group, (lxii) an aryloxy lower alkyl group (that may have as a substituent on the aryl group a group(s) selected from the group consisting of a lower alkoxy group, a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkoxy group and a lower alkyl group, and a pyrrolidinyl group that may have an oxo group(s)), (lxiii) an isoxazolidinyl group that may have an oxo group(s), (lxiv) a dihydroindenyl group, (lxv) an aryl lower alkoxy lower alkyl group, (lxvi) a tetrahydropyranyl group, (lxvii) an azetidinyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and an aroyl group, (lxviii) an azetidinyl lower alkyl group that may have a group(s) selected from the group consisting of a lower alkanoyl group and aroyl group, (lxix) a tetrazolyl group, (lxx) an indolinyl group that may have an oxo group(s), (lxxi) a triazolyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a lower alkylthio group, (lxxii) an imidazolyl group that may have a carbamoyl group(s), (lxxiii) an oxazolyl group that may have a lower alkyl group(s), (lxxiv) an isothiazolyl group that may have a lower alkyl group(s), (lxxv) a benzimidazolyl group, (lxxvi) a dihydrobenzothiazolyl group that may have an oxo group(s), (lxxvii) a thienyl group that may have a lower alkoxycarbonyl group(s), and (lxxviii) an oxazolyl lower alkyl group that may have a lower alkyl group(s), (29) an amino lower alkyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a halogen substituted lower alkyl group, a lower alkoxycarbonyl group, a lower alkanoyl group, an aryl group, an aryl lower alkyl group, an aroyl group, and an amino substituted alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group) on the amino group, (30) a lower alkyl group substituted with a carbamoyl group that may have a group(s) selected from the group consisting of a lower alkyl group and a halogen substituted lower alkyl group, (31) a thiocarbamoyl group that may have a lower alkyl group(s), (32) a sulfamoyl group, (33) an oxazolidinyl group that may have an oxo group(s), (34) an imidazolidinyl group that may have a substituent(s) selected from the group consisting of an oxo group and a lower alkyl group, (35) a pyrrolidinyl group that may have an oxo group(s), (36) an imidazolyl group, (37) a triazolyl group, (38) an isoxazolyl group, (39) a piperidyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, an arylsulfonyl group, an oxo group, a hydroxy group, and an amino group that may have a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and lower alkanoylamino lower alkanoyl group, (40) a piperidylcarbonyl group that may have a substituents) selected from the group consisting of a lower alkyl group, a hydroxy group, a hydroxy lower alkyl group, a lower alkanoyl group, a carboxy lower alkyl group, a lower alkyl carbamoyl lower alkyl group, a carbamoyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, an amino group (on which 1 to 2 groups selected from the group consisting of a lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group, and an aroyl group may be present), a piperidyl group (on which a group(s) selected from the group consisting of a lower alkanoyl group, a lower alkoxycarbonyl group, and an aroyl group may be present), a piperazinyl group (on which a lower alkyl group(s) may be present as a substituent), a 1,4-dioxa-8-azaspiro[4.5]decyl group, a morpholinyl group, a hexahydro-1,4-diazepinyl group (on which a lower alkyl group(s) may be present as a substituent), a pyridyl group, a pyridyloxy group, a pyridyl lower alkoxy group, a tetrahydroquinolyl group (on which an oxo group(s) may be present), a benzodioxolyl group, an aryl lower alkoxy group (that may have a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkoxy group on the aryl group), an aryl group (on which a group(s) selected from the group consisting of a halogen atom, a lower alkoxy group, and a hydroxy group may be present), an aryloxy group (that may have on the aryl group a group(s) selected from the group consisting of a cyano group, a halogen atom, lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), an aryl lower alkyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a halogen substituted lower alkyl group), and an aroyl group (that may have on the aryl group a group(s) selected from the group consisting of a halogen atom and a lower alkoxy group), (41) a pyrrolidinylcarbonyl group that may have a group as a substituent, selected from the group consisting of a hydroxy lower alkyl group, a carbamoyl group, a hydroxy group, an amino group (that may have on the amino group a group(s) selected from the group consisting of a lower alkyl group, a lower alkanoyl group, and an aroyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a piperidyl lower alkyl group, a piperazinyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperazinyl group), an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), an aryloxy group (that may have a halogen substituted lower alkoxy group(s) on the aryl group), an aryloxy lower alkyl group (that may have a halogen substituted lower alkoxy group(s) on the aryl group), and a tetrahydroquinolyl group (on which an oxo group(s) may be present), (42) a piperazinylcarbonyl group that may have a group(s) as a substituent, selected from the group consisting of a lower alkyl group, a cyclo C3-C8 alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl group, an amino lower alkyl group (that may have a lower alkyl group(s) as a substituent on the amino group), a piperidyl lower alkyl group (that may have a lower alkyl group(s) as a substituent on the piperidyl group), a morpholinyl lower alkyl group, a pyrrolidinyl lower alkyl group, a 1,3-dioxolanyl lower alkyl group, a tetrahydrofuryl lower alkyl group, a pyridyl lower alkyl group (that may have a phenyl group(s) as a substituent on the lower alkyl group), a imidazolyl lower alkyl group, a furyl lower alkyl group, a pyrrolidinylcarbonyl lower alkyl group, a piperidyl group (that may have a lower alkyl group(s) as a substituent), pyridyl group (that may have on the pyridyl group a group(s) selected from the group consisting of a lower alkyl group, a cyano group, and a halogen substituted lower alkyl group as a substituent), a thieno[2,3-b]pyridyl group, an aryl group (on which a group(s) selected from the group consisting of a halogen atom and a lower alkyl group may be present), an aroyl group, a furyl carbonyl group, an aryl lower alkoxycarbonyl group, and an oxo group, (43) a hexahydroazepinylcarbonyl group, (44) a hexahydro-1,4-diazepinylcarbonyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and a pyridyl group, (45) a dihydropyrroylcarbonyl group that may have a lower alkyl group(s), (46) a thiomorpholinylcarbonyl group, (47) a morpholinylcarbonyl group that may have a group(s) selected from the group consisting of a lower alkyl group, a piperidyl lower alkyl group, and an aryl group, (48) a thiazolidinyl carbonyl group that may have an aryl group(s) that may have a group(s) selected from the group consisting of a lower alkoxy group and a cyano group, (49) an azabicyclo[3.2.2]nonylcarbonyl group, (50) an 8-azabicyclo[3.2.1]octylcarbonyl group that may have a halogen substituted or unsubstituted aryloxy group(s), (51) an indolinylcarbonyl group, (52) a tetrahydroquinolylcarbonyl group, (53) a tetrahydropyrido[3.4-b]indolylcarbonyl group, (54) a morpholinyl lower alkyl group, (55) a piperazinyl lower alkyl group that may have a lower alkyl group(s) on the piperazinyl group, (56) a morpholinylcarbonyl lower alkyl group, (57) a piperazinylcarbonyl lower alkyl group that may have a lower alkyl group(s) on the piperazinyl group, (58) an oxo group, (59) an amino lower alkoxy group (that may have a lower alkyl group(s) on the amino group), (60) a lower alkoxy lower alkoxy group, (61) a piperazinyl group that may have a group(s) selected from the group consisting of an oxo group, a lower alkyl group, a lower alkanoyl group, and a lower alkoxycarbonyl group, (62) a morpholinyl group, (63) a 1,3,8-triazaspiro[4.5]decanylcarbonyl group that may have a group(s) selected from the group consisting of an oxo group and an aryl group, (64) a tetrahydropyridylcarbonyl group that may have a pyridyl group(s), (65) an imidazolidinylcarbonyl group that may have a thioxo group(s), and (66) a 1,4-dioxa-8-azaspiro[4.5]decanyl group. 